Alterations in vasomotor control of coronary resistance vessels in remodelled myocardium of swine with a recent myocardial infarction The mechanism underlying the progressive deterioration of left ventricular -LRB- LV -RRB- dysfunction after myocardial infarction -LRB- MI -RRB- towards overt heart failure remains incompletely understood , but may involve impairments in coronary blood flow regulation within remodelled myocardium leading to intermittent myocardial ischemia . Blood flow to the remodelled myocardium is hampered as the coronary vasculature does not grow commensurate with the increase in LV mass and because extravascular compression of the coronary vasculature is increased . In addition to these factors , an increase in coronary vasomotor tone , secondary to neurohumoral activation and endothelial dysfunction , could also contribute to the impaired myocardial oxygen supply . Consequently , we explored , in a series of studies , the alterations in regulation of coronary resistance vessel tone in remodelled myocardium of swine with a 2 to 3-week-old MI . These studies indicate that myocardial oxygen balance is perturbed in remodelled myocardium , thereby forcing the myocardium to increase its oxygen extraction . These perturbations do not appear to be the result of blunted β-adrenergic or endothelial NO-mediated coronary vasodilator influences , and are opposed by an increased vasodilator influence through opening of KATP channels . Unexpectedly , we observed that despite increased circulating levels of noradrenaline , angiotensin II and endothelin-1 , α-adrenergic tone remained negligible , while the coronary vasoconstrictor influences of endogenous endothelin and angiotensin II were virtually abolished . We conclude that , early after MI , perturbations in myocardial oxygen balance are observed in remodelled myocardium . However , adaptive alterations in coronary resistance vessel control , consisting of increased vasodilator influences in conjunction with blunted vasoconstrictor influences , act to minimize the impairments of myocardial oxygen balance . Introduction Heart failure constitutes a major cardiovascular disorder of which the incidence and prevalence are increasing , principally due to an increased survival of acute myocardial infarction -LRB- MI -RRB- in conjunction with an ageing population . The mechanism underlying the progressive deterioration of left ventricular -LRB- LV -RRB- dysfunction towards overt heart failure remains incompletely understood , but may involve -LRB- 1 -RRB- loss of cardiomyocytes through apoptosis -LSB- 75 -RSB- , -LRB- 2 -RRB- a primary reduction in contractile function of the surviving myocardium -LSB- 97 -RSB- , and/or -LRB- 3 -RRB- alterations in extracellular matrix leading to progressive LV dilation -LSB- 87 -RSB- . In addition , myocardial blood flow -LRB- MBF -RRB- abnormalities , resulting in impaired myocardial O2 delivery to the non-infarcted regions -LRB- leading to secondary contractile dysfunction and/or enhanced apoptosis -RRB- , have been suggested to contribute to the progression of LV dysfunction after MI -LSB- 99 -RSB- . For example , in vivo studies in rats -LSB- 54 , 55 -RSB- and swine -LSB- 108 -RSB- indicate a reduction in MBF reserve of up to 35 % in the surviving remodelled LV myocardium , 3 -- 8 weeks after infarction . Furthermore , in patients with overt heart failure -LSB- 94 -RSB- , but also in patients with only asymptomatic LV dysfunction -LSB- 95 -RSB- , flow reserve is reduced in the non-stenotic myocardial regions . In line with these clinical observations , we observed in a porcine model of post-infarct remodelling that during increased O2-demand induced by exercise , the increase in coronary blood flow -LRB- CBF -RRB- is impaired resulting in perturbations in oxygen delivery -LSB- 43 , 70 -RSB- . The reduction in flow reserve and the perturbed oxygen delivery during exercise are caused , at least in part , by insufficient growth of the coronary vasculature to maintain flow capacity commensurate with myocardial hypertrophy , in conjunction with a decrease in diastolic pressure time index resulting from the elevated heart rate and particularly elevated LV diastolic pressures -LSB- 43 -RSB- . In addition , coronary vasomotor tone may also be increased secondary to neurohumoral activation and endothelial dysfunction , further adding to the perturbations in CBF . However , little is known about the alterations in vasomotor control in coronary resistance vessels within remodelled myocardium -LRB- Fig. 1 -RRB- . For this reason we undertook a series of studies to determine whether neurohumoral -LRB- autonomic nervous system and renin-angiotensin system -RRB- , local metabolic , and endothelial control mechanisms of coronary resistance vessel tone are altered in swine with remodelled myocardium produced by a recent MI . Fig. 1Alterations in determinants of oxygen supply and demand in remodelled myocardium in swine with a 3-week-old myocardial infarction -LRB- MI -RRB- . The net effect of these alterations is a decrease in oxygen supply/demand ratio Characteristics of LV remodelling and dysfunction after MI in swine Left ventricular remodelling was produced by permanent ligation of the left circumflex coronary artery . This ligation results in a circumscribed transmural infarction of the lateral LV wall , comprising 20 -- 25 % of the total LV -LSB- 82 , 96 -RSB- . LV dysfunction in awake resting MI swine is characterised by 20 -- 30 % decreases in cardiac output , stroke volume and LVdP/dt max and a tripling of LV filling pressure . This difference between LVdP/dt max , cardiac output and stroke volume in normal and MI swine remained constant between ∼ 10 and ∼ 32 days , indicating that the degree of LV dysfunction and the circulatory adaptations in MI were stable during this observation period -LSB- 43 -RSB- . Similarly , we observed that already during the first week after infarction significant LV remodelling occurs , consisting of LV dilation and hypertrophy that remain fairly stable between 1 and 6 weeks after infarction -LSB- 98 -RSB- . During exercise , cardiac output , LV systolic pressure and LVdP/dt max increased almost in parallel in MI and normal animals up to 3 km/h , after which curves diverged -LRB- Fig. 2 -RRB- ; 4 km/h was also the maximally attainable exercise level for most MI swine . Fig. 2Cardiovascular responses to exercise in normal swine and swine with a ∼ 3-week-old MI . 0L = lying , 0S = standing . Data are mean ± SEM ; * P < 0.05 versus 0L , † P < 0.05 MI versus normal a corresponding exercise level . Data are from Haitsma et al. -LSB- 43 -RSB- Left ventricular dysfunction produced by MI results in neurohumoral activation , characterized by a trend towards elevated plasma levels of catecholamines , but normal circulating levels of renin , angiotensin II and aldosterone at rest . The latter may have been due to the increments in atrial natriuretic peptide -LRB- ANP -RRB- and endothelin , which can suppress renin and aldosterone release -LSB- 83 -RSB- . In resting MI swine , ANP doubled within 24 h , recovered to 50 % above normal values within 2 weeks and remained stable between 2 and 6 weeks after infarction , while renin and norepinephrine levels remained normal under resting conditions -LSB- 98 -RSB- . In contrast to the discrete neurohumoral activation in resting swine with MI , exercise resulted in exaggerated increases in catecholamines and ANP and increases in endothelin , angiotensin II , and aldosterone -LRB- Fig. 3 -RRB- . While resting circulating levels of norepinephrine were still normal and the relative sympathetic drive in response to exercise was preserved in MI , the cardiac responsiveness to exercise -LRB- both heart rate and LVdP/dt max -RRB- was already blunted 3 weeks after infarction -LSB- 43 -RSB- , likely due to β-adrenoceptor desensitization and/or downregulation -LSB- 100 -RSB- . Fig. 3Neurohumoral responses in exercising swine with a ∼ 3-week-old MI . In the norepinephrine , epinephrine and dopamine panels , data shown for N represent 0L , 1 , 2 , 3 , 4 and 5 km/h and data for MI represent 0L , 1 , 2 , 3 and 4 km/h . In all other panels , data shown for N represent 0L , 1 , 3 and 5 km/h and data for MI represent 0L , 1 , 3 and 4 km/h . Mean data points were fitted with second order curves . VO2 = O2-consumption . Data are mean ± SEM ; * P < 0.05 vs 0L , † P < 0.05 MI versus Normal . Data are from Haitsma et al -LSB- 43 -RSB- Myocardial O2 balance in remodelled myocardium Marked decreases in myocardial perfusion occur in pacing-induced severe heart failure in swine -LSB- 88 -RSB- and dogs -LSB- 85 , 90 -RSB- , especially in the more vulnerable subendocardial layers . Although one study in dogs indicated that the lower MBF is principally the result of a lower myocardial O2 consumption -LRB- MVO2 -RRB- -LSB- 90 -RSB- , studies in swine suggest that the impaired perfusion is , at least in part , responsible for the deterioration of LV function because the interstitial edema and disruption of collagen fibers in the subendocardium resemble the ultrastuctural changes that occur with recurrent ischemia -LSB- 49 , 89 -RSB- . In animal models of severe pressure-overload induced LV hypertrophy , selective underperfusion of the subendocardium can produce myocardial ischemia during exercise and result in post-exercise myocardial stunning -LSB- 2 , 102 -RSB- . The contribution of perfusion abnormalities in the remote surviving myocardium to LV dysfunction after a MI remains unclear . Studies in rats demonstrated a 25 -- 40 % reduction in coronary flow reserve in the surviving myocardium at four -LSB- 55 -RSB- and eight -LSB- 54 -RSB- weeks after MI . Similarly , maximum subendocardial blood flow was blunted by 40 % in anesthetized swine with heart failure 3 weeks after a MI -LSB- 108 -RSB- . We hypothesized that the decreased flow reserve could limit the increase in MBF to the hypertrophied myocardium during exercise when hemodynamic abnormalities and neurohumoral activation are exacerbated , thereby impairing myocardial O2-supply . Three weeks after infarction , blood flow per gram of myocardium in the -LRB- remote -RRB- LV anterior wall of resting swine with MI was similar to that in normal animals -LRB- Fig. 4 -RRB- , confirming previous studies in rats and swine -LSB- 54 , 55 , 108 -RSB- . Interestingly , we observed a trend towards slightly higher blood flows in the outer two layers -LRB- P = 0.09 -RRB- , suggesting that despite hypertrophy of the surviving myocardium , metabolic demand in the outer , but not the inner , layers was still slightly elevated , 3 weeks after infarction -LSB- 43 -RSB- . During exercise , MBF increased but was redistributed in favor of the subepicardium in MI compared to normal swine . These perturbations were most likely due to increased extravascular compressive forces , resulting from a reduction in diastolic time fraction -LRB- secondary to impaired relaxation and increased heart rate -RRB- and elevated LV filling pressures -LSB- 43 , 97 -RSB- , that impede MBF , particularly in the subendocardial layers . The decreased MBF necessitated a small increase in O2 extraction that resulted in a slightly lower coronary venous O2 tension -LRB- Fig. 4 -RRB- , which actually may have been underestimated as the lower myocardial capillary density in swine with MI possibly prevented a greater increase in O2 extraction -LSB- 43 , 70 -RSB- . The observation that O2 extraction was forced to increase indicates that increases in extravascular forces are not fully compensated by a concomitant lowering of coronary vasomotor tone in remodelled myocardium during exercise . These observations prompted us to further investigate the control of coronary vasomotor tone in remodelled myocardium during exercise . Fig. 4Myocardial blood flow and O2-balance in the left ventricular anterior wall of N and MI ∼ 3 weeks after myocardial infarction . Epi subepicardial , OM outer mid ; IM inner mid ; Endo subendocardial . MVO2 = myocardial O2-consumption ; MEO2 = myocardial O2 extraction ; CVPO2 = coronary venous O2 tension In the top left panel data myocardial blood flow data are shown for resting -LRB- Rest , lying -RRB- conditions , and during maximum exercise -LRB- Ex , 5 km/h in N and 4 km/h in MI -RRB- . Data are mean ± SEM ; * P < 0.05 versus 0L , † P < 0.05 MI versus Normal . Data are from Haitsma et al -LSB- 43 -RSB- Vasomotor control of the coronary microcirculation in remodelled myocardium Neurohumoral control Cardiac dysfunction is accompanied by a hemodynamic defense reaction consisting of salt and water retention , peripheral vasoconstriction and cardiac stimulation , which serves to partially restore cardiac output and to increase systemic vascular resistance in order to maintain arterial pressure -LSB- 56 -RSB- . An integral part of this defense reaction involves alterations in autonomic balance , consisting of an increase in sympathetic activity and a decrease in parasympathetic activity -LSB- 56 -RSB- . Sympathetic control In patients with advanced heart failure plasma noradrenaline levels are already increased under resting conditions -LSB- 11 , 36 -RSB- . These increased levels result principally from increased sympathetic nerve activity although impaired reuptake may also contribute -LSB- 56 -RSB- . Prolonged exposure to elevated noradrenaline levels results in desensitization and downregulation of the β-adrenergic receptors -LSB- 8 , 32 , 101 -RSB- . During exercise , the increases in catecholamine levels are exaggerated in patients with heart failure as compared to healthy controls -LSB- 35 -RSB- , which is aimed at maintaining chronotropic and inotropic responses to exercise -LSB- 34 -RSB- . Also in swine with LV dysfunction produced by a 2 -- 3-week-old MI , we observed exaggerated increases in arterial and coronary venous catecholamine levels during treadmill exercise -LSB- 23 , 43 -RSB- , at a time when resting catecholamine levels were still in the normal range -LSB- 43 , 98 -RSB- . The exaggerated exercise-induced increases in catecholamine levels reflect increased sympathetic activity , which acts to maintain the chronotropic and inotropic responses to acute exercise . This concept is supported by the observation that β-adrenoceptor blockade produced slightly greater decreases in the chronotropic response during exercise in MI as compared to normal swine . In contrast , β-adrenoceptor blockade in MI swine resulted in a smaller decrease in global LV contractility compared to normal swine , in particular during exercise . The latter findings are consistent with a reduced left ventricular myocardial β-adrenoceptor responsiveness -LSB- 100 -RSB- . In normal swine and dogs , β-adrenergic receptor activation contributes to coronary vasodilatation during exercise -LSB- 27 , 39 -RSB- . The β-adrenergic coronary vasodilatation results in an increase in myocardial oxygen delivery that is commensurate with the increase in oxygen consumption , so that myocardial oxygen extraction and hence coronary venous O2 tension remain constant -LRB- Fig. 5 -RRB- . In MI swine , the net β-adrenergic vasodilator influence on the coronary circulation is maintained . However , in view of the exaggerated increases in catecholamine levels during exercise , these findings suggest a diminished β-adrenergic responsiveness of the coronary resistance vessels after MI . Fig. 5Effect of saline , α-adrenoceptor blockade -LRB- phentolamine , 1 mg/kg iv -RRB- and/or β-adrenoceptor blockade -LRB- propranolol , 0.5 mg/kg iv -RRB- and of muscarinic receptor blockade -LRB- atropine , 30 μg/kg/min , iv -RRB- and/or β-adrenoceptor blockade -LRB- propranolol , 0.5 mg/kg iv -RRB- on the response of coronary venous O2 tension -LRB- CVPO2 -RRB- plotted as a function of myocardial O2 consumption -LRB- MVO2 -RRB- in seven normal and 7 MI swine . * P < 0.05 versus corresponding Control ; † P < 0.05 Atropine + Propranolol versus corresponding Atropine or Phentolamine + Propranolol versus corresponding Phentolamine ; Data are mean ± SEM . Data are from Duncker et al. -LSB- 23 -RSB- In dogs , α-adrenoceptor activation limits the exercise-induced increase in CBF , thereby necessitating an increase in myocardial O2 extraction , which leads to a decrease in coronary venous O2 tension -LSB- 39 , 51 -RSB- . In contrast , α-adrenoceptors do not contribute to regulation of coronary blood flow in normal swine during exercise -LSB- 27 -RSB- . We found that , in accordance with our findings in normal swine , administration of the α-adrenoceptor blocker phentolamine had also no effect on coronary venous O2 tension of MI swine -LRB- Fig. 5 -RRB- . These findings indicate that even in the presence of exaggerated increments in catecholamine levels in MI swine during exercise , α-adrenoceptors do not contribute to regulation of tone in porcine coronary resistance vessels -LSB- 23 -RSB- . Parasympathetic control The shift in the sympathovagal balance , with an increased sympathetic activity -LSB- 12 , 33 -RSB- and a blunted parasympathetic activity is reflected in reduced heart rate variability and reduced baroreceptor reflex sensitivity -LSB- 6 , 12 , 30 , 76 -RSB- in patients with advanced heart failure . We observed that a maximal dose of the muscarinic receptor blocker atropine produced a similar increase in resting heart rate in swine with MI as compared to normal swine , suggesting preserved parasympathetic activity under resting conditions -LSB- 23 -RSB- . In contrast , the atropine-induced increase in heart rate during exercise -LRB- particularly at higher exercise levels -RRB- was blunted in MI swine , while the increase in LVdP/dt max was abolished -LSB- 23 -RSB- . These results are consistent with the concept that gradual inhibition of parasympathetic influence on the heart during exercise was more pronounced in swine with MI compared to normal swine . Importantly , these findings suggest that after MI , at a time when parasympathetic tone under basal resting conditions is normal , a more pronounced inhibition of parasympathetic tone occurs with increasing exercise intensity . Since parasympathetic activity can presynaptically modulate sympathetic activity -LSB- 1 -RSB- , it is likely that the greater degree of withdrawal of parasympathetic tone during exercise contributed to the exaggerated increase in sympathetic activity during exercise . This is also supported by the observation that in the presence of propranolol , the effects of atropine were no longer different between MI and normal swine -LSB- 23 -RSB- . In resting dogs , parasympathetic activity exerts a direct vasodilator influence on coronary resistance vessels that is mediated via nitric oxide -LSB- 109 -RSB- . In contrast , in resting swine parasympathetic activity exerts an indirect vasoconstrictor effect on the coronary resistance vessels -LRB- which wanes at increasing exercise intensity -RRB- that is mediated via inhibition of β-adrenergic vasodilatation -LSB- 27 -RSB- . In contrast to the loss of the inhibitory influence of the parasympathetic system on β-adrenoceptor mediated cardiostimulation , we observed that its effects on the coronary circulation were maintained in MI compared to normal swine -LRB- Fig. 5 -RRB- -LSB- 23 -RSB- . These findings indicate that at this stage of LV dysfunction , parasympathetic control of β-adrenoceptor-mediated coronary vasodilatation is unimpaired . Angiotensin II The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume , blood pressure and vascular tone . Angiotensin II -LRB- ANG-II -RRB- exerts its effects on vascular tone through binding to the AT1-receptor , resulting in vasoconstriction , as well as binding to the AT2-receptor , evoking vasodilation -LSB- 14 -RSB- . Both receptor subtypes have been identified in the coronary microcirculation -LSB- 4 , 107 -RSB- , suggesting that endogenous ANG-II may contribute to the regulation of coronary vascular tone and to the regulation of myocardial perfusion . Under pathological circumstances , i.e. after MI , the renin-angiotensin system is activated , resulting in increased plasma levels of ANG-II , particularly during exercise -LSB- 34 , 43 -RSB- . Moreover , there is evidence that AT1-receptor density in the viable region of the myocardium is increased early after MI -LSB- 62 , 98 -RSB- , suggesting that its vasoconstrictor influence on the coronary vasculature could be increased , which may limit myocardial perfusion thereby exacerbating LV dysfunction . Contrary to our hypothesis , we observed a loss of ANG-II induced vasoconstrictor influence , reflected by the lack of increase in coronary venous O2 tension -LRB- Fig. 6 -RRB- , despite increased plasma ANG-II levels and maintained AT1 receptor densities in coronary arterioles isolated from remodelled myocardium of MI swine -LSB- 68 -RSB- . It is unlikely that a generalized loss of vasodilator capacity in the remote myocardium contributed to the blunted vasodilator response to the AT1 receptor blocker irbesartan , as we have previously shown that vasodilation produced by nitroprusside is unperturbed -LSB- 44 -RSB- . Although an increased AT2-receptor expression could have acted to limit ANG-II induced vasoconstriction -LSB- 84 -RSB- this is unlikely as AT2-mRNA was not altered in coronary arteries from patients with ischemic heart disease -LSB- 103 -RSB- . Moreover , the dramatic increases in ANG-II levels that we observed after irbesartan did not result in enhanced , but rather blunted , coronary vasodilation -LSB- 68 -RSB- . Therefore , the observation of a reduced vasoconstrictor influence of endogenous ANG-II is best explained by AT1-receptor-desensitization , which is in accordance with studies in dogs with pacing-induced heart failure -LSB- 78 -RSB- , in rats with pressure-overload LV hypertrophy -LSB- 63 -RSB- , and in rats with LV remodeling after MI -LSB- 84 -RSB- , that demonstrated blunted vasoconstrictor responses to exogenous ANG-II . Fig. 6Effect of AT1-receptor blockade with irbesartan -LRB- 1 mg/kg iv -RRB- on the relation between myocardial O2 consumption -LRB- MVO2 -RRB- and coronary venous O2 tension -LRB- CVPO2 -RRB- in normal swine and swine with a 2 -- 3-week-old myocardial infarction . Data are means ± SE ; * P < 0.05 versus corresponding control relation , † P < 0.05 effect of irbesartan different in MI versus Normal animals . Data are from Merkus et al. -LSB- 68 -RSB- Local metabolic control Adenosine Adenosine has been proposed to be a metabolic messenger that regulates coronary resistance vessel tone in response to changes in metabolic needs of the myocardium -LSB- 5 -RSB- . However , adenosine receptor blockade with 8 PT and/or augmenting adenosine catabolism with intracoronary adenosine deaminase had either no effect -LSB- 3 -RSB- or produced a small decrease -LSB- 28 , 67 , 93 -RSB- in basal coronary venous O2 tension -LRB- reflecting vasoconstriction -RRB- , but did not interfere with the normal exercise-induced increase in CBF and O2 delivery -LSB- 3 , 28 , 67 , 93 -RSB- , indicating that adenosine is not critical for the exercise-induced coronary vasodilation or that loss of adenosine-mediated vasodilation can be compensated for by increased contribution of other vasodilator pathways to maintain adequate metabolic vasodilation . In contrast to the lack of evidence for an essential role of adenosine in regulation of CBF under physiological conditions , endogenously released adenosine does contribute to coronary vasodilation when there is insufficient supply of O2 -LSB- 61 -RSB- . Similarly , adenosine production could be increased in the remodelled myocardium after MI as a result of the perturbations in the myocardial O2 balance -LSB- 43 , 70 , 108 -RSB- . However , we found no evidence for an increased contribution of adenosine to regulation of coronary resistance vessel tone in remodelled myocardium of swine with a recent MI -LSB- 71 -RSB- , as adenosine receptor blockade with 8 PT caused a similar decrease in coronary venous O2 tension in post-infarct remodelled hearts and normal hearts both at rest and during exercise -LRB- Fig. 7 -RRB- . These findings are in agreement with observations in dogs with pressure-overload LV hypertrophy , in which adenosine receptor blockade did not affect CBF either at rest or during exercise -LSB- 65 -RSB- . Fig. 7Effect of the adenosine receptor antagonist 8-phenyltheophylline -LRB- 8 PT , 5 mg/kg iv -RRB- , the KATP channel blocker glibenclamide -LRB- Glib , 3 mg/kg iv -RRB- or their combination on myocardial O2 balance in the LV anterior free wall of normal swine and swine with a recent MI . MVO2 = myocardial O2 consumption ; CVPO2 = coronary venous O2 tension ; Data are mean ± SEM ; Data are mean ± SEM ; * P ≤ 0.05 versus corresponding control ; † P ≤ 0.05 effect of Glib was blunted at higher MVO2 levels -LRB- Glib × MVO2 -RRB- ; ‡ P ≤ 0.05 effect of Glib different after MI -LRB- Glib × MVO2 × MI -RRB- . Data are from Merkus et al. -LSB- 71 -RSB- Several reasons could be forwarded for the failure to observe a larger contribution of adenosine to regulation of coronary resistance vessel tone . First , it is possible that the perturbations in the myocardial O2 balance were too mild to increase adenosine production . Second , the activity of enzymes that regulate tissue adenosine levels may have been altered -LSB- 16 , 17 -RSB- . For example , the activity of adenosine deaminase , the enzyme responsible for breakdown of adenosine to inosine , was found to be elevated in LV hypertrophy -LSB- 10 , 13 , 15 -RSB- . Furthermore , there is evidence that the activity of cytosolic 5 ′ nucleotidase , which converts 5 ′ AMP to adenosine , is lower in certain models of pressure-overload -LSB- 13 -RSB- and volume-overload -LSB- 10 -RSB- induced LV hypertrophy , which could be related to intermittent hypoperfusion of the hypertrophic myocardium -LSB- 41 -RSB- . Together these enzymatic alterations , which act to decrease myocardial levels of adenosine may have prevented a significant increase in myocardial adenosine levels in the post MI remodelled hearts . Finally , it is possible that an increased role of adenosine in hypertrophied myocardium is masked by an increased contribution of other vasodilator systems during adenosine receptor blockade , as the process of metabolic vasodilation is thought to be mediated through multiple parallel or redundant pathways . Thus , KATP channel activity may have increased in response to adenosine receptor blockade to compensate for the loss of adenosine-mediated vasodilation . Hence , we evaluated the interactions between these vasodilator pathways . KATP channels In addition to the role of KATP channels in the regulation of CBF under physiological conditions -LSB- 24 , 25 , 31 -RSB- , there is evidence for an increased KATP channel activity in the coronary circulation of remodelled hearts . For example , in anesthetized dogs with pacing-induced severe heart failure -LSB- 106 -RSB- , the KATP channel blocker glibenclamide resulted in an exaggerated vasoconstrictor response as compared to normal dogs . Interestingly , in dogs subjected to only 1 week of pacing -LRB- when LV function was still normal -RRB- , KATP channel activity was not different from normal dogs -LSB- 106 -RSB- , suggesting that KATP channel activity in the basal resting state was only enhanced in the presence of overt heart failure . Similarly , in awake dogs with compensated pressure-overload induced LV hypertrophy , the reduction in CBF produced by glibenclamide was similar to that in normal dogs -LSB- 65 -RSB- . During exercise , however , glibenclamide produced a greater reduction in CBF in hypertrophied hearts , indicating increased KATP-channel contribution to coronary vasodilation when O2 requirements of the hypertrophied heart were augmented -LSB- 65 -RSB- . In swine with MI-induced moderate LV remodeling and dysfunction , glibenclamide caused a marked decrease in coronary venous O2 tension in remodelled left ventricle under resting conditions , that was similar to the decrease in coronary venous O2 tension in normal hearts -LRB- Fig. 7 ; -LSB- 71 -RSB- -RRB- . Although the vasoconstriction under resting conditions in response to KATP channel blockade was similar in normal and post-MI remodelled hearts , the responses to exercise were different . Thus in normal swine , the effects of KATP channel blockade waned during exercise , suggesting that other vasodilator systems compensated for the loss of KATP channels during exercise . In contrast , in the post-MI remodelled hearts the effects of KATP channel blockade were maintained during exercise . Our findings , which are consistent with the observations in dogs -LSB- 65 -RSB- , support the hypothesis that KATP channel opening is of greater importance in resistance vessel dilation during exercise in hypertrophied than in normal hearts . It is likely that with the progression from LV dysfunction to overt heart failure , increased KATP channel activity may also become important under resting conditions -LSB- 106 -RSB- . Interaction between KATP channels and adenosine In contrast to the canine heart in which adenosine can act as a back-up system -LSB- 29 , 81 -RSB- , adenosine and KATP channels appear to exert additive vasodilator influences on coronary vasomotor tone in the normal porcine heart -LSB- 67 -RSB- . Thus , the coronary vasoconstriction that occurs in response to combined adenosine receptor blockade and KATP channel blockade equalled the sum of the vasoconstriction induced by blockade of the individual pathways . Adenosine mediates its vasodilator effect on porcine coronary resistance vessels via KATP , KCa and Kv channels -LSB- 9 , 46 -- 48 -RSB- It is therefore possible that following KATP channel blockade adenosine maintained its vasodilator influence via KCa and/or Kv channels . In contrast to the normal porcine heart , the magnitude of the constriction induced in remodelled hearts by combined blockade of adenosine receptors and KATP channels was virtually identical to that produced by blockade of KATP channels alone -LSB- 71 -RSB- . These findings could be interpreted to suggest that in remodelled myocardium the vasodilator influence of endogenous adenosine was entirely mediated through opening of KATP channels , observations that are corroborated by findings in pressure-overload hypertrophied canine hearts -LSB- 65 -RSB- . Taken together these observations in the porcine and canine coronary circulations suggest that , although the magnitude of the vasodilator influence exerted by endogenous adenosine was similar in normal and remodelled hearts , its effector pathway was different . Endothelial control Several studies have indicated that endothelial dysfunction , in particular a decreased production of NO and an increased production of endothelin , could aggravate LV dysfunction due to the peripheral vasoconstriction-induced increase in LV afterload , coronary vasoconstriction , and increased myocardial O2 consumption -LSB- 26 , 59 , 80 , 105 -RSB- . Nitric oxide Clinical studies indicate that chronic heart failure is accompanied by blunted vasodilator responses to endothelium-dependent receptor mediated vasodilators -LRB- particularly acetylcholine -RRB- in the microcirculation of the LV myocardium -LSB- 92 -RSB- , leg -LSB- 45 , 57 -RSB- , and forearm -LSB- 19 , 52 , 57 , 64 -RSB- . In the canine model of pacing-induced end-stage congestive heart failure , attenuated vasodilator responses of resistance vessels to acetylcholine in vivo have also been observed in the microvasculature of the hindleg circulation -LSB- 22 , 64 -RSB- and the coronary circulation -LSB- 105 -RSB- . In swine with a 2 -- 3-week-old MI , we observed reduced vasodilator responses in the systemic and coronary microvasculature to ATP , in doses which we have previously shown to be completely abolished by pretreatment with the eNOS-inhibitor NLA -LSB- 26 -RSB- . The findings of a blunted ATP-induced vasodilation are in agreement with the hypothesis that agonist-induced eNOS-mediated NO production is blunted 2 -- 3 weeks after MI . A loss of NO-mediated vasodilation could enhance the progression of LV dysfunction to heart failure . This is supported by studies in dogs with pacing-induced dilated cardiomyopathy , in which the loss of basal NO production in the LV myocardium coincides with the progression from LV dysfunction to overt heart failure -LSB- 80 , 105 -RSB- . However , in swine with a 2 -- 3-week-old MI , we did not find any evidence of a reduced coronary vasodilator influence of endogenous NO as decreases in coronary venous O2 tension produced by NLA in resting and exercising MI swine were similar to those of normal swine -LRB- Fig. 8 -RRB- . In heart failure patients , studies on the contribution of NO to basal microvascular tone in the forearm , leg , or total systemic bed have yielded equivocal results with responses varying from blunted -LSB- 45 , 58 , 64 -RSB- , to maintained -LSB- 60 -RSB- , and even enhanced -LSB- 20 , 42 -RSB- increases in vascular tone following NO synthase inhibition . It is possible that a maintained or increased NO production as observed in some studies , was the result of increased iNOS expression -LSB- 21 , 79 -RSB- , as part of a generalized inflammatory response in end-stage heart failure , that occurred in the presence of either a decreased -LSB- 21 , 86 -RSB- or increased -LSB- 37 , 50 -RSB- eNOS expression . Since NLA can block all three isoforms of NOS -LSB- 7 -RSB- , we performed additional experiments , in which we blocked iNOS with aminoguanidine , to determine whether an upregulation of iNOS-mediated NO production masked a reduction in eNOS activity . iNOS blockade had no effect on coronary vasomotor tone , demonstrating that NO production via iNOS does not contribute significantly to vascular tone in MI swine , and , consequently , that basal and exercise-induced endothelial NO production is maintained early after MI -LSB- 44 -RSB- . Fig. 8Effect of inhibition of NO synthase by NLA -LRB- 20 mg/kg iv -RRB- on myocardial O2 extraction and coronary venous PO2 at rest -LRB- lying -RRB- and during treadmill exercise in MI and N. Data are mean ± SEM . * P < 0.05 NLA versus corresponding Control ; there were no significant differences in the responses to NLA between MI and N either at rest or during exercise . Data are from Haitsma et al. -LSB- 44 -RSB- The reason for the maintained basal and exercise-induced NO production in the presence of a blunted vasodilator response to ATP is unclear . However , Traverse et al. -LSB- 91 -RSB- have shown that the amount of NO , produced after stimulation with an agonist is larger than the amount of NO produced during moderate exercise -LRB- 60 % increase in heart rate -RRB- . Hence , the maximal capacity of NO production may be reduced , whereas the capacity of eNOS is sufficient to maintain basal and exercise-induced NO production . This explanation is unlikely since agonist-induced dilation is already affected at the lowest dose of administered ATP -LRB- which probably releases less NO than strenuous exercise -RRB- . Moreover , higher doses of ATP still produce more dilation . Another explanation for the divergent results between ATP and exercise-induced increases in NO-production may be that ATP activates eNOS through a different mechanism than shear stress . ATP-induced activation of eNOS is mediated through a calcium-calmodulin dependent pathway -LSB- 74 -RSB- whereas shear stress activates eNOS through Akt-mediated phosphorylation -LSB- 18 -RSB- , resulting in calcium-independent activation of eNOS . Hence , it is possible that perturbations in the calcium homeostasis of endothelial cells contributed to the selective impairment of ATP-induced vasodilation in swine with MI . Endothelin Despite the increased plasma levels of endogenous ET in swine with a 2 -- 3 week old MI , its vasoconstrictor influence on the coronary circulation was reduced -LRB- Fig. 9 -LSB- 69 , 70 -RSB- -RRB- . To determine whether this was the result of blunted receptor responsiveness or reduced local ET-production , we studied the vasoconstriction induced by exogenous ET . The coronary vasoconstrictor influence to exogenous ET-1 in vivo was reduced after MI , indicating a reduced coronary vascular responsiveness to ET . Paradoxically , a recent study showed that ischemic heart disease results in upregulation of ETA and ETB receptor mRNA in human coronary arteries -LSB- 104 -RSB- . This is in accordance with our measurements in isolated coronary arterioles obtained from sham-operated swine and swine with a MI , which showed that the ET responsiveness in vessels from animals with a MI was actually increased -LSB- 70 -RSB- . The discrepancy between the in vivo and the in vitro findings suggests that ET receptor sensitivity is modulated in vivo , and that this modulation is apparently lost in vitro . Possible modulators of ET-receptor sensitivity are adenosine and NO , which have been shown to desensitize ET-receptors on the coronary vasculature -LSB- 72 , 73 -RSB- , and which may have been lost in the in vitro set-up due to lack of surrounding myocardium and intravascular blood flow . However , since we observed similar vasoconstrictor responses to blockade of adenosine receptors and NO production in MI and normal swine , these vasodilators would seem unlikely explanations for the observed reduced ET receptor sensitivity in MI swine in vivo . Fig. 9Effect of ETA receptor blockade with EMD -LRB- 3 mg/kg iv -RRB- on myocardial oxygen balance in normal swine and swine with a recent MI . Data are means ± SE ; * P < 0.05 versus corresponding Control relation , † P < 0.05 effect of EMD waned during exercise . Data are from Merkus et al. -LSB- 70 -RSB- In conclusion , our observations suggest that when additional coronary vasodilation is required in the hypertrophied myocardium after MI , withdrawal of the ET-mediated vasoconstrictor influence contributes to a shift in vasomotor tone towards vasodilation . These findings may also explain in part why clinical trials of ET-receptor antagonists in heart failure have failed to show therapeutic value of these compounds -LSB- 40 , 77 -RSB- . Conclusions and physiological relevance Under physiological circumstances , the heart matches its blood supply to the demand of the myocardium by altering the balance of vasodilator and vasoconstrictor influences , i.e. an increase in myocardial O2 demand results in an increased influence of vasodilators -LRB- opening of KATP channels , NO , adenosine -LSB- 53 -RSB- , β-adrenergic vasodilation -LSB- 27 -RSB- -RRB- and a decreased influence of the potent vasoconstrictor endothelin-1 -LSB- 66 , 69 -RSB- . Studies from our laboratory performed during the past 10 years have shown that following MI myocardial O2 balance in the remodelled LV is perturbed , necessitating vasodilation and recruitment of coronary flow reserve , as evidenced by increased opening of KATP channels -LSB- 71 -RSB- . Importantly , however , not only an increased KATP channel vasodilator influence , but also blunting of the coronary vasoconstrictor influences of endogenous endothelin -LSB- 70 -RSB- and angiotensin II -LSB- 68 -RSB- , aid in preventing a more significant impairment of oxygen supply to the remodelled myocardium -LRB- Figs. 10 , 11 -RRB- . Our studies suggest that generalized blunting of vasoconstrictor influences is one of the first adaptive mechanisms to reduce coronary resistance vessel tone and increase myocardial blood supply . This adaptation , which occurs in the healthy porcine heart during acute exercise , also appears operative in remodelled myocardium . Blunting of vasoconstrictor influences may be a physiologically favorable strategy , since it is more energy-efficient to blunt vasoconstrictor influences than to synthesize vasodilators . Fig. 10Myocardial oxygen balance in normal and MI swine . Shown are the actual relations between MVO2 and CVPO2 in 30 normal swine -LRB- open circles -RRB- and 20 MI swine -LRB- open triangles -RRB- under control conditions . In addition , we have depicted the computed relations in MI swine if the ET -LRB- solid diamonds -RRB- and ANG II -LRB- solid squares -RRB- vasoconstrictor influences -LRB- which were both attenuated in MI swine -RRB- and the KATP -LRB- solid triangles -RRB- vasodilator influences -LRB- which were enhanced in MI swine -RRB- would have been identical to those in normal swine . The graph clearly illustrates that the adaptations in coronary vasomotor control act to blunt perturbations in oxygen balance in remodelled myocardium of swine with a recent MI Fig. 11Alterations in vasomotor balance in the coronary resistance vessels within remodelled myocardium in swine with a 2 -- 3-week-old myocardial infarction Although the shift in coronary tone towards vasodilatation acts to blunt the flow perturbations in the remodelled heart , it does not appear to fully restore myocardial oxygen balance . This is also supported by the observation that KATP channel activation is increased , consistent with the presence of metabolic distress . Whether these perturbations in myocardial oxygen delivery blood are sufficiently severe to contribute to the progressive deterioration of contractile function of the remodelled left ventricle remains to be established , but it is of interest to note that we previously found that troponin I proteolysis occurred in remodelled myocardium , which was associated with a loss of myofilament force development -LSB- 97 -RSB- . Intermittent myocardial ischemia , as may occur in remodelled hearts during exercise or excitement , has been shown to be able to promote troponin I proteolysis -LSB- 38 -RSB- and could thereby mediate the flow perturbation-induced progressive deterioration of LV function after MI . Definitive proof of our hypothesis must await future studies demonstrating that prevention of such flow perturbations will indeed prevent progressive loss of contractile function of the remodelled porcine left ventricle .

O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O B O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O B O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O B O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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exercise


Ensuring

the

Safe

and

Effective

Use

of

Medications

During

Pregnancy

Planning

and

Prevention

Through

Preconception

Care

Introduction

Whether

to

use

a

medication

during

pregnancy

can

be

a

concern

for

both

women

and

health

care

providers

It

has

been

estimated

that

up

to

of

congenital

anomalies

may

be

caused

by

environmental

exposures

that

is

exposures

to

medications

alcohol

or

other

exogenous

factors

that

have

adverse

effects

on

the

developing

embryo

or

fetus

-LSB-

-RSB-

Avoiding

all

potentially

adverse

exposures

can

prevent

these

adverse

effects

However

it

is

not

always

possible

to

avoid

taking

medications

during

pregnancy

Women

who

are

pregnant

continue

to

experience

short-term

and

long-term

health

conditions

that

must

be

managed

Discontinuing

treatment

of

a

serious

condition

when

a

woman

becomes

pregnant

can

have

profound

long-term

implications

both

for

her

health

and

that

of

her

baby

In

a

retrospective

study

from

eight

health

maintenance

organizations

researchers

estimated

that

approximately

of

pregnant

women

were

prescribed

a

medication

other

than

a

vitamin

or

mineral

supplement

at

some

time

during

pregnancy

-LSB-

-RSB-

Use

of

over-the-counter

medications

during

pregnancy

may

be

even

higher

and

many

women

take

a

dietary

or

herbal

supplement

other

than

multivitamins

or

folic

acid

while

pregnant

-LSB-

-RSB-

Preconception

care

provides

the

opportunity

to

optimize

a

woman

's

use

of

medications

in

preparation

for

pregnancy

Such

care

includes

identifying

patterns

of

medication

use

before

pregnancy

occurs

adjusting

those

patterns

to

avoid

the

use

of

nonessential

medications

minimizing

exposure

to

medications

known

to

be

harmful

to

the

embryo

or

fetus

and

adjusting

the

dose

route

of

administration

and

timing

of

essential

treatments

to

optimize

maternal

health

at

each

stage

of

pregnancy

while

safeguarding

the

embryo

fetus

and

infant

In

this

paper

we

summarize

the

basic

principles

of

teratology

and

the

current

state

of

knowledge

about

the

effects

of

medication

use

during

pregnancy

outline

basic

components

of

preconception

care

that

can

help

minimize

the

risk

of

birth

defects

and

provide

examples

of

approaches

to

planning

for

the

safe

and

effective

use

of

medications

during

pregnancy

through

preconception

care

Principles

of

teratology

The

term

teratogen

is

sometimes

used

to

describe

an

agent

that

can

produce

structural

or

functional

abnormalities

in

a

developing

embryo

or

fetus

Although

this

implies

that

an

agent

is

inherently

either

teratogenic

or

not

teratogenicity

is

actually

a

property

of

the

exposure

taken

as

whole

not

only

the

physical

and

chemical

nature

of

the

agent

but

also

the

dose

route

of

administration

and

timing

in

gestation

as

well

as

concurrent

exposure

to

other

agents

and

biological

susceptibility

of

the

mother

and

embryo

or

fetus

The

developmental

stage

of

the

embryo

or

fetus

at

the

time

of

exposure

is

critical

During

conception

and

for

about

weeks

thereafter

most

cells

of

the

conceptus

are

not

yet

committed

to

a

specific

developmental

program

One

damaged

cell

can

be

replaced

by

another

and

normal

development

will

usually

ensue

although

the

embryo

will

not

survive

if

too

many

cells

are

damaged

or

killed

This

is

known

as

the

all-or-nothing

period

but

even

during

this

period

some

exposures

can

adversely

affect

the

development

of

surviving

embryos

-LSB-

-RSB-

The

subsequent

period

of

organogenesis

from

to

days

after

conception

-LRB-

about

weeks

after

the

start

of

the

last

normal

menstrual

period

-RRB-

is

the

time

of

greatest

sensitivity

to

most

teratogenic

exposures

Fetal

exposure

later

in

gestation

usually

does

not

produce

gross

structural

abnormalities

although

there

are

exceptions

Adverse

exposures

during

the

fetal

period

more

often

result

in

growth

restriction

or

functional

disorders

of

the

central

nervous

system

kidneys

or

other

organs

Dose

is

a

critical

feature

of

any

teratogenic

exposure

Teratogenic

effects

occur

only

when

the

dose

of

an

agent

exceeds

a

certain

threshold

-LSB-

-RSB-

Medications

that

are

generally

considered

safe

during

pregnancy

can

have

adverse

effects

on

the

embryo

or

fetus

if

the

mother

takes

them

in

doses

that

are

so

high

that

they

cause

maternal

toxicity

Chronic

exposure

is

usually

of

more

concern

than

a

single

exposure

if

the

doses

are

similar

The

route

of

exposure

is

also

important

For

example

risk

is

unlikely

from

the

use

of

dermal

agents

that

lack

substantial

systemic

absorption

The

teratogenicity

of

an

exposure

is

also

influenced

by

both

the

maternal

and

fetal

genotypes

which

can

result

in

differences

in

cell

sensitivity

placental

transport

metabolism

receptor

binding

or

drug

distribution

Some

medications

are

metabolized

extensively

by

the

mother

their

teratogenicity

depends

upon

whether

a

toxic

form

reaches

the

embryo

or

fetus

in

sufficient

quantities

to

produce

adverse

effects

Current

state

of

knowledge

about

the

effects

of

medication

use

during

pregnancy

Maternal

effects

Many

women

begin

pregnancy

with

medical

conditions

that

require

ongoing

or

episodic

treatment

Examples

include

asthma

epilepsy

and

hypertension

In

addition

other

medical

problems

such

as

migraine

headache

or

auto-immune

disorders

may

be

exacerbated

by

pregnancy

When

planning

for

the

management

of

maternal

conditions

during

pregnancy

it

is

important

to

distinguish

conditions

for

which

withholding

treatment

could

be

harmful

to

the

mother

embryo

or

fetus

from

those

for

which

cessation

of

treatment

is

unlikely

to

pose

significant

risk

For

example

women

with

major

depression

who

discontinue

antidepressant

medication

before

conception

are

at

high

risk

of

relapse

and

consequent

self-injurious

or

even

suicidal

behavior

-LSB-

-RSB-

In

contrast

cessation

of

treatment

for

moderate

hypercholesterolemia

with

a

statin

drug

while

a

woman

is

pregnant

is

unlikely

to

increase

her

cardiovascular

morbidity

or

mortality

significantly

Physiologic

changes

occur

during

pregnancy

that

can

alter

the

effective

dose

of

medications

a

woman

is

taking

Some

changes

occur

abruptly

while

others

evolve

slowly

Most

begin

during

the

first

trimester

and

peak

during

the

second

trimester

of

pregnancy

-LSB-

-RSB-

It

may

be

necessary

to

adjust

the

dose

and/or

frequency

of

medication

use

repeatedly

during

pregnancy

Physiologic

changes

that

can

affect

the

pharmacokinetics

and/or

pharmacodynamics

of

medications

during

pregnancy

include

Changes

in

total

body

weight

and

body

fat

composition.Delayed

gastric

emptying

prolonged

gastrointestinal

transit

time

and

decreased

gastric

acid

secretion

all

of

which

can

affect

the

bioavailability

of

drugs

-LSB-

-RSB-

Expanded

plasma

volume

and

significantly

increased

extracellular

fluid

space

and

total

body

water

content

These

vary

with

the

patient

's

weight

and

can

affect

the

volume

of

distribution

of

drugs

-LSB-

-RSB-

Increased

cardiac

output

stroke

volume

heart

rate

and

blood

flow

to

the

uterus

kidneys

skin

and

mammary

glands

The

percentage

of

cardiac

output

attributed

to

hepatic

blood

flow

is

lower

during

pregnancy

-LSB-

-RSB-

Decreased

concentration

of

plasma

albumin

which

can

reduce

the

protein

binding

of

some

drugs

-LSB-

-RSB-

Increased

glomerular

filtration

rate

early

in

pregnancy

with

a

continued

rise

throughout

pregnancy

-LSB-

-RSB-

Changes

in

the

activity

of

hepatic

enzymes

including

the

cytochrome

enzymes

xanthine

oxidase

and

N-acetyltransferase

-LSB-

-RSB-

Unfortunately

there

are

relatively

few

studies

of

drug

pharmacokinetics

during

pregnancy

The

dose

of

medications

usually

prescribed

during

pregnancy

is

the

same

used

in

nonpregnant

adults

but

this

may

result

in

substantial

under

or

over-dosage

during

pregnancy

When

blood

or

serum

concentrations

of

medications

can

be

measured

and

the

most

effective

level

is

known

they

should

be

monitored

throughout

pregnancy

and

appropriate

dosage

adjustments

made

as

needed

Further

well-designed

and

well-conducted

pharmacokinetic

and

pharmacodynamic

studies

of

medications

during

pregnancy

are

needed

Fetal

effects

Maternal

treatment

with

conventional

doses

of

some

medications

during

a

susceptible

period

of

pregnancy

is

known

to

be

harmful

to

the

developing

embryo

Thalidomide

and

isotretinoin

are

the

most

notable

examples

but

there

are

others

-LSB-

-RSB-

In

contrast

taking

some

other

medications

or

dietary

supplements

such

as

folic

acid

helps

to

prevent

adverse

pregnancy

outcomes

-LSB-

-RSB-

Because

pregnant

women

are

traditionally

excluded

from

clinical

trials

for

ethical

reasons

and

because

premarketing

animal

studies

do

not

necessarily

predict

the

effects

of

treatment

in

human

pregnancy

little

information

about

the

teratogenic

risks

or

safety

of

most

drugs

is

available

at

the

time

they

are

marketed

Animal

teratology

studies

are

not

routinely

conducted

for

non-prescription

drugs

vitamins

and

dietary

and

herbal

supplements

although

these

substances

may

produce

pharmacological

or

toxic

effects

in

the

fetus

Moreover

there

is

no

standard

requirement

for

studies

of

adverse

effects

among

children

of

women

who

took

a

drug

during

pregnancy

after

it

has

been

approved

by

the

FDA

In

a

review

conducted

in

researchers

found

that

there

was

not

enough

information

to

assess

the

teratogenic

risk

or

safety

during

human

pregnancy

of

more

than

of

prescription

medications

approved

by

the

FDA

in

the

previous

years

-LSB-

-RSB-

Even

when

available

studies

addressing

fetal

effects

of

maternal

medication

use

during

pregnancy

may

provide

conflicting

results

or

insufficient

information

to

assess

all

potential

outcomes

or

levels

of

risk

The

concept

of

safety

implies

the

absence

of

risk

which

is

impossible

to

demonstrate

conclusively

with

any

kind

of

study

Thus

it

can

be

difficult

for

women

and

health

care

providers

to

decide

whether

to

use

a

medication

during

pregnancy

The

balance

of

risk

benefit

and

efficacy

of

treatment

for

both

mother

and

fetus

is

not

always

clear

and

must

be

individualized

for

different

women

under

different

circumstances

Basic

components

of

preconception

care

that

can

minimize

the

risk

of

birth

defects

Serious

congenital

anomalies

including

chromosome

abnormalities

and

Mendelian

disorders

can

be

identified

in

about

of

infants

at

birth

-LSB-

-RSB-

However

some

anomalies

do

not

become

apparent

until

later

in

life

-LSB-

-RSB-

While

most

birth

defects

are

not

preventable

some

can

be

avoided

through

appropriate

planning

and

medical

interventions

The

following

components

of

preconception

care

can

help

minimize

the

risk

of

birth

defects

Optimize

health

before

conception

occurs

This

includes

counseling

women

to

avoid

smoking

use

of

excessive

alcohol

and

illicit

drugs

and

exposure

to

potentially

toxic

environmental

or

occupational

hazards

before

they

are

pregnant.Establish

effective

treatment

for

chronic

conditions

before

conception

occurs.Carefully

manage

all

chronic

conditions

and

intercurrent

illnesses

throughout

pregnancy.Counsel

women

to

avoid

the

use

of

nonessential

medications

including

prescription

and

over-the-counter

medications

and

dietary

or

herbal

supplements.Avoid

the

use

of

medications

with

high

teratogenic

risk

when

equally

effective

treatments

with

lower

risks

are

available.Limit

the

use

of

essential

medications

to

the

smallest

number

of

drugs

possible

that

will

effectively

treat

maternal

disease

without

compromising

the

health

of

the

woman

or

her

fetus.Limit

each

essential

medication

to

the

smallest

dose

that

can

be

used

to

effectively

treat

maternal

disease

without

compromising

the

health

of

the

woman

or

her

fetus.Recommend

that

all

women

who

are

capable

of

becoming

pregnant

take

a

vitamin

supplement

or

eat

fortified

foods

to

assure

consumption

of

mg

-LRB-

micrograms

-RRB-

of

folic

acid

per

day

Effective

pregnancy

management

in

women

with

chronic

conditions

requires

careful

planning

close

medical

supervision

before

and

during

pregnancy

and

continuous

communication

between

the

pregnant

woman

and

her

health

care

providers

Examples

of

approaches

to

preconception

planning

for

the

use

of

medications

during

pregnancy

in

different

clinical

settings

Exactly

how

the

components

of

preconception

planning

for

the

use

of

medications

during

pregnancy

are

implemented

depends

on

the

nature

of

the

condition

requiring

treatment

the

known

risks

and

safety

of

use

of

the

specific

drugs

during

pregnancy

and

the

woman

's

individual

circumstances

among

other

factors

In

this

section

we

provide

three

examples

of

approaches

to

planning

for

the

safe

and

effective

use

of

medications

in

clinical

settings

where

these

factors

vary

Avoiding

teratogenic

treatments

for

non

life-threatening

maternal

conditions

isotretinoin

Isotretinoin

is

indicated

for

the

treatment

of

severe

nodular

cystic

acne

unresponsive

to

other

therapy

but

is

also

used

to

treat

non-nodular

but

scarring

acne

A

single

course

of

therapy

typically

lasts

weeks

and

can

result

in

complete

and

prolonged

remission

of

the

acne

in

many

patients

However

isotretinoin

treatment

in

the

first

trimester

of

pregnancy

is

teratogenic

Exposed

infants

can

have

craniofacial

cardiac

thymic

and

central

nervous

system

malformations

-LSB-

-RSB-

Research

has

also

shown

a

high

incidence

of

developmental

delay

in

children

whose

mothers

used

isotretinoin

early

in

the

first

trimester

regardless

of

whether

the

children

had

structural

malformations

-LSB-

-RSB-

Isotretinoin

is

indicated

for

use

only

in

men

and

nonpregnant

women

It

should

never

be

used

during

pregnancy

However

because

approximately

half

of

pregnancies

in

the

United

States

are

unintended

some

women

use

isotretinoin

in

the

early

weeks

of

gestation

before

realizing

they

are

pregnant

-LSB-

-RSB-

Teratogenic

outcomes

have

been

reported

after

only

one

dose

of

isotretinoin

during

pregnancy

-LSB-

-RSB-

The

half-life

of

isotretinoin

is

approximately

h

but

about

weeks

are

required

to

eliminate

of

the

drug

from

the

body

after

cessation

of

use

Several

risk

management

strategies

have

been

implemented

to

prevent

the

use

of

isotretinoin

during

pregnancy

but

pregnancy

exposures

continue

to

occur

-LSB-

-RSB-

An

enhanced

risk

management

program

called

iPLEDGE

became

fully

operational

in

March

-LSB-

-RSB-

iPLEDGE

is

a

single

mandatory

program

for

all

marketed

isotretinoin

products

It

requires

that

wholesalers

pharmacies

doctors

and

patients

register

with

the

program

in

order

to

obtain

the

drug

Female

patients

who

are

capable

of

having

children

must

obtain

counseling

about

the

risks

of

isotretinoin

treatment

and

the

requirements

for

its

safe

use

complete

an

informed

consent

form

have

two

negative

pregnancy

tests

documented

before

starting

isotretinoin

therapy

use

two

different

forms

of

contraception

simultaneously

or

agree

not

to

engage

in

heterosexual

intercourse

for

one

month

prior

to

starting

isotretinoin

throughout

the

course

of

treatment

and

for

one

month

after

completing

treatment

and

have

a

negative

pregnancy

test

documented

every

month

during

treatment

and

one

month

after

completing

treatment

More

information

about

the

iPLEDGE

program

can

be

found

at

Preconception

care

provides

a

unique

and

critical

opportunity

to

prevent

exposure

to

teratogens

such

as

isotretinoin

Any

woman

who

is

considering

pregnancy

should

be

asked

whether

she

is

taking

any

medications

including

any

preparation

containing

isotretinoin

If

so

her

health

care

provider

should

emphasize

the

risks

of

isotretinoin

use

during

pregnancy

reevaluate

the

need

for

and

duration

of

treatment

assess

thoroughly

the

use

and

effectiveness

of

contraceptive

measures

and

reinforce

the

key

elements

of

the

iPLEDGE

program

Women

should

be

informed

that

conception

can

not

be

attempted

without

risk

of

teratogenicity

until

one

full

month

after

the

last

dose

of

isotretinoin

was

taken

Educational

information

and

materials

from

the

iPLEDGE

program

can

also

be

helpful

in

the

setting

of

preconception

care

Managing

maternal

conditions

that

require

continuous

treatment

epilepsy

At

least

one

in

every

pregnant

women

or

about

takes

an

anticonvulsant

drug

-LSB-

-RSB-

Approximately

half

take

the

drugs

to

prevent

seizures

but

anticonvulsants

are

also

used

to

manage

mood

disorders

migraine

headaches

and

chronic

pain

Anticonvulsant

drugs

have

several

different

modes

of

action

such

as

targeting

a

specific

receptor

or

enzyme

-LSB-

-RSB-

As

a

result

anticonvulsant

medications

vary

in

their

effectiveness

for

specific

types

of

epilepsy

Individuals

with

epilepsy

may

respond

differently

to

particular

medications

reflecting

genetic

differences

such

as

polymorphisms

in

the

cytochrome

enzymes

It

is

not

yet

possible

to

screen

for

pharmacogenetic

differences

that

would

help

select

the

appropriate

anticonvulsant

for

individual

use

Physiologic

changes

during

pregnancy

also

can

affect

the

disposition

of

anticonvulsant

drugs

and

the

dose

needed

to

prevent

seizures

-LSB-

-RSB-

While

not

all

anticonvulsant

drugs

have

been

studied

in

pregnancy

a

number

of

adverse

effects

have

been

identified

in

infants

and

children

of

women

treated

with

these

medications

during

pregnancy

Major

malformations

midface

and

digit

hypoplasia

microcephaly

growth

restriction

and

deficits

in

IQ

are

sometimes

seen

although

the

pattern

of

abnormalities

and

specific

effects

vary

for

individual

drugs

-LSB-

-RSB-

For

example

spina

bifida

occurs

in

approximately

of

fetuses

exposed

to

carbamazepine

and

in

to

of

fetuses

exposed

to

valproic

acid

-LSB-

-RSB-

microcephaly

and

growth

restriction

are

observed

more

frequently

in

infants

whose

mothers

took

two

or

more

anticonvulsant

drugs

simultaneously

during

pregnancy

-LSB-

-RSB-

and

subtle

effects

on

intelligence

have

been

identified

in

some

studies

of

children

exposed

to

carbamazepine

phenytoin

or

phenobarbital

in

utero

although

developmental

delay

and

deficits

in

cognitive

function

are

much

more

frequent

with

exposure

to

valproic

acid

-LSB-

-RSB-

While

some

infants

exposed

to

an

anticonvulsant

drug

in

utero

have

abnormalities

others

do

not

Genetic

differences

in

the

fetal

response

to

medications

probably

play

a

role

It

has

been

hypothesized

that

maternal

epilepsy

might

cause

fetal

abnormalities

independent

of

any

drug

effect

but

several

studies

suggest

that

anticonvulsant

treatments

are

usually

responsible

-LSB-

-RSB-

However

it

seems

likely

that

repeated

or

prolonged

maternal

seizures

such

as

occur

in

status

epilepticus

can

be

devastating

to

the

fetus

-LSB-

-RSB-

Discontinuation

or

inadequate

treatment

of

maternal

epilepsy

may

be

more

dangerous

to

the

fetus

than

effective

anticonvulsant

therapy

Preconception

care

provides

an

opportunity

to

choose

a

plan

of

anticonvulsant

treatment

that

will

pose

the

least

risk

to

the

fetus

while

appropriately

managing

maternal

symptoms

New

data

about

the

effects

on

the

fetus

of

anticonvulsant

medications

are

emerging

steadily

and

the

latest

information

should

always

be

sought

The

treatment

plan

must

be

individualized

for

each

woman

in

collaboration

with

her

neurologist

psychiatrist

or

other

specialist

Primary

considerations

include

assessing

whether

taking

an

anticonvulsant

drug

is

essential

to

the

mother

's

health

using

the

fewest

number

of

anticonvulsant

drugs

possible

using

the

lowest

dose

for

each

drug

that

will

effectively

treat

maternal

symptoms

-LSB-

-RSB-

establishing

the

most

effective

blood

level

of

each

drug

before

conception

and

monitoring

drug

levels

throughout

pregnancy

For

carbamazepine

phenobarbital

phenytoin

primidone

and

valproic

acid

levels

of

the

non-protein

bound

or

free

concentration

should

be

measured

Because

abrupt

cessation

of

a

medication

may

result

in

increased

seizures

or

exacerbation

of

other

symptoms

the

number

and

dose

of

medications

should

be

adjusted

and

the

woman

's

response

stabilized

over

a

period

of

time

before

attempting

conception

In

addition

preconception

care

offers

the

opportunity

to

consider

whether

additional

measures

such

as

the

use

of

a

higher

daily

dose

of

folic

acid

might

be

beneficial

Only

limited

and

somewhat

conflicting

information

is

available

about

whether

periconceptional

supplementation

with

folic

acid

at

levels

higher

than

mg

per

day

decreases

the

risk

for

neural

tube

defects

associated

with

anticonvulsant

drug

exposure

in

utero

-LSB-

-RSB-

Currently

many

women

who

require

anticonvulsant

drug

therapy

during

pregnancy

take

or

mg

of

folic

acid

daily

Managing

maternal

conditions

with

intermittent

symptoms

asthma

Asthma

is

a

chronic

condition

with

intermittent

symptoms

for

which

treatment

during

pregnancy

is

essential

to

safeguard

the

health

and

well-being

of

both

the

mother

and

fetus

Abrupt

cessation

or

undertreatment

of

asthma

during

pregnancy

can

endanger

both

Studies

suggest

that

maternal

asthma

during

pregnancy

can

increase

the

risk

for

perinatal

mortality

preeclampsia

preterm

delivery

and

low

birth

weight

-LSB-

-RSB-

Maternal

asthma

can

lead

to

alkalosis

with

decreased

blood

flow

to

the

uterus

decreased

venous

return

and

a

leftward

shift

of

the

oxyhemoglobin

dissociation

curve

all

of

which

may

contribute

to

fetal

hypoxia

In

the

extreme

maternal

hypoxia

can

result

in

decreased

umbilical

blood

flow

increased

systemic

and

pulmonary

vascular

resistance

in

the

fetus

and

decreased

fetal

cardiac

output

Fetal

compromise

may

occur

well

before

maternal

symptoms

become

severe

-LSB-

-RSB-

Additional

pathophysiologic

mechanisms

that

could

contribute

to

these

adverse

outcomes

include

hyperactivity

of

uterine

and

bronchial

smooth

muscle

and

the

release

of

bioactive

mediators

during

symptomatic

asthma

-LSB-

-RSB-

For

these

reasons

it

is

considered

safer

for

pregnant

women

to

be

treated

with

asthma

medications

than

to

experience

asthma

symptoms

and

exacerbations

-LSB-

-RSB-

A

variety

of

medications

are

available

to

treat

acute

and

chronic

asthma

They

include

corticosteroids

cromolyn

leukotriene

modifiers

theophylline

and

anticholinergics

These

drugs

have

different

mechanisms

of

action

and

thus

potentially

different

effects

on

the

fetus

Before

attempting

conception

it

is

important

to

maximize

asthma

control

using

medications

that

can

also

be

used

to

manage

asthma

symptoms

during

pregnancy

This

will

ensure

maximum

oxygen

delivery

to

the

developing

embryo

and

fetus

while

avoiding

unintended

medication

exposures

A

period

of

time

may

be

needed

to

wean

patients

off

some

medications

and

to

stabilize

symptoms

using

others

before

attempting

conception

In

addition

because

an

estimated

one

third

of

pregnant

women

with

asthma

experience

an

increase

in

the

frequency

or

severity

of

their

symptoms

during

pregnancy

it

is

important

to

develop

a

plan

before

conception

occurs

for

regular

monitoring

of

asthma

symptoms

and

pulmonary

function

during

pregnancy

and

for

early

recognition

and

prompt

treatment

of

exacerbations

-LSB-

-RSB-

This

plan

should

include

a

review

of

the

proper

use

of

medications

including

the

proper

technique

for

using

inhalers

education

about

self-monitoring

and

self-management

at

home

and

specific

instructions

about

when

to

contact

a

health

professional

for

additional

care

The

National

Asthma

Education

and

Prevention

Program

Working

Group

outlines

a

step-wise

approach

for

managing

asthma

during

pregnancy

in

its

report

Managing

Asthma

During

Pregnancy

Recommendations

for

Pharmaceutical

Treatment

Update

This

report

was

developed

after

a

systematic

review

of

the

current

evidence

from

safety

studies

of

asthma

medications

during

pregnancy

-LSB-

-RSB-

The

approach

is

centered

on

the

use

of

and

corticosteroids

by

inhalation

when

possible

to

minimize

systemic

absorption

The

dose

frequency

and

number

of

medications

are

decreased

when

possible

but

increased

as

needed

and

pulmonary

function

is

measured

regularly

-LRB-

e.g.

by

monthly

spirometry

testing

-RRB-

during

pregnancy

The

approach

also

emphasizes

the

need

for

a

treatment

plan

tailored

to

each

patient

's

needs

and

circumstances

the

frequency

and

severity

of

her

symptoms

and

her

individual

response

to

treatment

Regardless

of

the

specifics

the

benefits

and

risks

of

asthma

treatment

and

of

uncontrolled

asthma

during

pregnancy

for

both

the

mother

and

fetus

should

be

discussed

during

preconception

planning

so

that

a

fully

informed

plan

for

asthma

management

can

be

agreed

upon

Additional

measures

can

be

instituted

preconceptionally

to

minimize

the

severity

or

frequency

of

asthma

symptoms

during

pregnancy

and

thus

decrease

reliance

on

and

fetal

exposure

to

medications

Identifying

reducing

or

eliminating

exposure

to

allergens

such

as

animal

dander

house-dust

mites

cockroaches

pollen

and

indoor

mold

to

irritants

such

as

perfumes

sprays

and

cleaning

agents

and

to

smoke

including

primary

and

secondhand

tobacco

smoke

wood

burning

stoves

or

fireplaces

may

decrease

asthma

symptoms

Preconception

counseling

also

provides

an

opportunity

to

discuss

the

use

of

over-the-counter

medications

for

symptoms

such

as

rhinitis

congestion

and

esophageal

reflux

that

are

often

associated

with

asthma

While

over-the-counter

medications

can

be

purchased

without

a

prescription

they

contain

pharmacologically

active

ingredients

that

may

affect

the

fetus

For

example

studies

have

suggested

that

use

of

pseudoephedrine

or

aspirin

in

the

first

trimester

may

increase

the

risk

of

gastroschisis

a

rare

abdominal

wall

defect

-LSB-

-RSB-

It

has

been

theorized

that

gastroschisis

could

result

from

vascular

disruption

Both

aspirin

and

pseudoephedrine

can

have

vasoactive

effects

although

the

causal

pathway

has

not

been

established

for

either

drug

and

the

absolute

risk

of

their

use

is

very

small

Most

over-the-counter

medications

have

not

been

adequately

studied

in

pregnancy

Conclusion

Although

it

is

always

better

to

avoid

unnecessary

medical

treatment

during

pregnancy

some

women

with

chronic

conditions

may

not

be

able

to

become

pregnant

without

appropriate

therapy

In

many

other

cases

proper

treatment

of

a

chronic

condition

during

pregnancy

may

be

safer

for

both

the

woman

and

her

baby

than

stopping

this

treatment

It

is

important

that

women

who

are

planning

a

pregnancy

talk

with

their

health

care

provider

before

beginning

a

new

medication

or

making

changes

in

current

medications

for

the

management

of

acute

or

chronic

conditions

Continuous

communication

between

a

pregnant

woman

and

her

health

care

providers

careful

preconceptional

planning

effective

management

of

conditions

prior

to

pregnancy

and

close

medical

supervision

during

pregnancy

can

help

assure

the

best

possible

outcome

for

every

woman

and

baby

New

information

about

the

effects

of

medication

use

and

the

optimal

management

of

maternal

conditions

during

pregnancy

continually

becomes

available

The

following

are

regularly

updated

sources

of

such

information

and

advice

The

Organization

of

Teratology

Information

Specialists

-LRB-

OTIS

-RRB-

provides

medical

consultation

usually

by

phone

to

individuals

and

health

care

providers

about

the

reproductive

risks

of

prenatal

exposures.Phone

is

an

information

source

for

laboratory

scientists

practicing

physicians

and

government

agencies

that

contains

commentaries

on

the

effects

of

chemicals

and

physical

agents

on

human

pregnancy

reproduction

and

development.Website

Teratogen

Information

System

-LRB-

TERIS

-RRB-

is

a

computerized

database

of

summaries

of

individual

agents

designed

to

assist

health

care

professionals

in

assessing

the

risks

of

exposures

in

pregnant

women

Each

summary

is

based

on

a

review

of

the

published

literature

and

includes

a

risk

assessment

derived

by

consensus

of

an

advisory

board

of

authorities

in

clinical

teratology.Website

Information

about

the

results

of

premarketing

studies

of

individual

medications

including

animal

reproductive

studies

and

human

clinical

trials

is

usually

available

from

the

drug

manufacturer

A

list

of

many

of

the

existing

postmarketing

pregnancy

registries

that

seek

to

monitor

exposure

to

specific

medications

during

pregnancy

is

maintained

by

the

Office

of

Women

's

Health

U.S.

Food

and

Drug

Administration

at

Additional

information

is

available

from

the

March

of

Dimes

at

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O B O B 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O O O O O B O O O O O O O O B O O O O B O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B B O O O B O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O B B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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