bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of phasic velocities in vessels of intact freely beating hearts
Authors: Nellis S. H. , Carroll K. L. , Eggleston A. M.
Published: December 2017

The study of flow dynamics on the coronary microcirculation of the intact beating heart has been greatly hampered by the thickness of the tissue and its continual movement. Using fluorescent microspheres and video-image processing, we have devised a means to measure an index of blood velocities. Measurements were made on open-chest anesthetized cats without any artificial restraints to the heart motion. However, advantages exist for minimizing mechanical motion, therefore, a heart holder based on a vacuum concept, along with modified versions of previously demonstrated methods, were tested. Results showed that the vacuum holder provided more restraint to epicardial motion than the pericardium alone, and despite large differences in epicardial motion between the two, overall flow measurements of the microspheres were comparable. Other methods of immobilizing the heart usually did not yield normal flow velocities. This video analysis method allows for the reproducible measurement of particle velocities at time points throughout the cardiac cycle. In keeping the normal heart dynamics intact, more realistic results from the study of coronary blood flows can be obtained.
N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs
Authors: Fineman J. R. , Heymann M. A. , Soifer S. J.
Published: December 2017

To investigate the role of endothelium-derived relaxing factor (EDRF) in the regulation of resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation, we studied the hemodynamic effects of N omega-nitro-L-arginine (a new stereospecific EDRF inhibitor) in 10 spontaneously breathing lambs and then compared the hemodynamic responses to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimetic) or N omega-nitro-L-arginine. N omega-nitro-L-arginine caused a significant dose-dependent increase in pulmonary arterial pressure. Pretreatment with L-arginine blocked this increase, but pretreatment with D-arginine did not, suggesting that N omega-nitro-L-arginine is a competitive inhibitor of L-arginine for EDRF production. During U-46619 infusions, acetylcholine, ATP-MgCl2, isoproterenol, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) decreased pulmonary arterial pressure. During N omega-nitro-L-arginine infusions, the decrease in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) was significantly attenuated, but the decrease caused by isoproterenol, sodium nitroprusside, and 8-bromo-cGMP (endothelium-independent vasodilators) was unchanged. This study supports the hypothesis that EDRF in part mediates resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation. N omega-nitro-L-arginine is useful for studying EDRF inhibition in intact animals.
Role of baroreceptor afferents on area postrema-induced inhibition of sympathetic activity
Authors: Hay M. , Hasser E. M. , Undesser K. P. , Bishop V. S.
Published: December 2017

Activation of the area postrema by either electrical stimulation or chemical application of L-glutamate has been shown to result in an enhancement of cardiovascular baroreflexes similar to that seen with systemic infusions of arginine vasopressin (AVP). In addition, it has been found that the effects of AVP on baroreflex inhibition of renal sympathetic nerve activity (RSNA) are similar to those observed with phenylephrine following lesions of the area postrema or after partial denervation of baroreceptor afferents. The present study was undertaken to determine the role of baroreceptor afferent input on area postrema stimulation-induced decreases in sympathetic activity. In anesthetized rabbits, the responses of arterial pressure, heart rate, and RSNA to area postrema electrical stimulation were obtained before and after progressive sinoaortic denervation and vagotomy. Stimulation of the area postrema in carotid sinus-denervated animals consistently decreased RSNA in a frequency-dependent manner. However, following bilateral removal of both the aortic nerves and the vagi, electrical stimulation of the area postrema had no effect on RSNA. These results suggest that the ability of area postrema stimulation to inhibit RSNA is dependent on the presence of baroreceptor afferent input.
Adrenergic facilitation of myogenic response in skeletal muscle arterioles
Authors: Meininger G. A. , Faber J. E.
Published: December 2017

The myogenic response was studied in large skeletal muscle arterioles in the presence of varying degrees of constriction with norepinephrine (NE; 3 x 10(-8) to 1 x 10(-5) M) or potassium chloride (KCl, 40-120 mM). The cremaster muscle of anesthetized rats was exteriorized into a Krebs-filled tissue bath chamber for observation of the microvasculature using a video microscopy system. The body of the rats was enclosed in an airtight Plexiglas box that was pressurized from 0 to +30 mmHg to raise intravascular pressure and elicit the myogenic response. All experiments were performed in acutely denervated muscles with propranolol (1 x 10(-6) M) present to produce beta-receptor blockade. Diameter responses of the first-order arteriole (1A) were measured with a videoimage caliper and intravascular pressure with the servo-null micropipette technique. Under basal conditions, without NE, 1A diameter increased in a passivelike fashion from 122 +/- 5.4 to 130 +/- 5.1 microns as box pressure was elevated from 0 to +30 mmHg, respectively. Addition of NE to the cremaster bath produced a dose-dependent constriction of the 1A (EC50 2 x 10(-7) M). In the presence of this adrenergic tone the 1A exhibited myogenic constriction in response to increases in box pressure. For example, topical application of 3 X 10(-7) M NE caused the 1A to constrict from 122 +/- 5.4 to 70 +/- 5.3 microns. In the presence of this adrenergic tone elevating box pressure from 0 to +30 mmHg caused additional constriction to 55 +/- 6.6 microns.(ABSTRACT TRUNCATED AT 250 WORDS)
Age-related changes in responses to nerve stimulation and catecholamines in isolated monkey cerebral arteries
Authors: Toda N.
Published: December 2017

Mechanical responses to transmural electrical stimulation, nicotine, norepinephrine, and isoproterenol were compared in cerebral artery strips obtained from Japanese monkeys of different ages (1 mo, 1 yr, 4–7 yr, and greater than 7 yr old). Transmural electrical stimulation produced a contraction in the baby and juvenile monkey arteries contracted with prostaglandin F2 alpha, whereas the older monkey arteries responded to the stimulation with a relaxation. The stimulation-induced contraction was abolished or reversed to a relaxation by phentolamine; the relaxation was not influenced by propranolol and atropine but was abolished by tetrodotoxin, as was the response of the mature monkey arteries. Contractions caused by norepinephrine were greater in baby cerebral arteries than in the older monkey arteries; however, the apparent median effective concentration values did not differ. Middle cerebral artery contractions were greater than those of basilar arteries. The norepinephrine-induced contraction was suppressed by prazosin but not influenced by yohimbine. Isoproterenol (up to 10(-6) M) produced a greater relaxation in the baby arteries than in the older monkey arteries. It is suggested that adrenergic nerves innervating immature monkey cerebral arteries contribute to the regulation of vascular tone predominantly over nonadrenergic, noncholinergic vasodilator nerves, whereas the vasodilator nerves play a major role in the mature monkey arteries. alpha 1-Adrenoceptor subtype appears to be mainly involved in the norepinephrine-induced contraction of baby monkey cerebral arteries, as it is in that of the adult monkey arteries.
Cardiac dysfunction after acute endotoxin administration in conscious sheep
Authors: Sugi K. , Newald J. , Traber L. D. , Maguire J. P. , Herndon D. N. , Schlag G. , Traber D. L.
Published: December 2017

We evaluated cardiac function in an unanesthetized ovine model of hyperdynamic endotoxemia. The animals were instrumented for crystallographic dimension analysis of the left ventricle (LV) and measurement of LV, aortic, atrial, central venous, and pulmonary arterial pressures, and cardiac output. Seven sheep received 1.5 micrograms/kg of Escherichia coli endotoxin [lipopolysaccharide (LPS) LPS-P group] and were compared to a sham group. The sham group demonstrated no significant change in any of the variables. In the LPS-P group, the cardiac index increased (5.7 +/- 0.4 to 7.9 +/- 0.6 l.min-1.m-2) between 8 and 12 h after LPS. Concomitantly, the maximum elastance of LV end-systolic pressure-volume relations significantly decreased (2.88 +/- 0.27 mmHg/ml) compared with baseline (3.89 +/- 0.50 mmHg/ml). Other indexes of the LV contractility (maximum pressure development and ejection fraction) were also reduced. There was a simultaneous increase in the LV end-systolic and diastolic volumes. These findings confirm the hypothesis that there is a myocardial depression during LPS in the ovine model.
Adrenergic vasoconstriction limits coronary blood flow during exercise in hypertrophied left ventricle
Authors: Bache R. J. , Homans D. C. , Dai X. Z.
Published: December 2017

This study was carried out to test the hypothesis that alpha-adrenergic vasoconstriction limits coronary blood flow (CBF) during exercise in the chronically pressure overloaded, hypertrophied left ventricle. Studies were performed in dogs in which left ventricular hypertrophy had been produced by banding the ascending aorta at 9 wk of age. Left circumflex coronary artery blood flow and myocardial O2 consumption (MVO2) were examined at rest and during treadmill exercise during control conditions, after selective alpha 1-adrenergic blockade with prazosin, and after nonselective alpha-adrenergic blockade with phentolamine. All studies were performed after beta-adrenergic blockade with propranolol. During control conditions CBF and MVO2 increased progressively during exercise, while coronary sinus O2 tension decreased. Neither prazosin nor phentolamine altered CBF at rest but, in comparison with control measurements, both agents significantly increased CBF during exercise and abolished the decrease in coronary sinus O2 tension that normally occurred during exercise. Both prazosin and phentolamine caused similar significant increases of MVO2 relative to the heart rate times systolic left ventricular pressure during exercise, indicating that the increased CBF produced by these agents enhanced MVO2. Similar findings after prazosin and phentolamine indicate that adrenergic restraint of CBF during exercise resulted principally from alpha 1-adrenergic vasoconstrictions with little additional contribution from postjunctional alpha 2-adrenergic mechanisms.
Prostaglandin F2 alpha-induced endothelium-dependent relaxation in isolated monkey cerebral arteries
Authors: Kawai Y. , Ohhashi T.
Published: December 2017

Effects of prostaglandin F2 alpha (PGF2 alpha) on isolated monkey and dog cerebral arteries were investigated to reevaluate PGF2 alpha's possible action on the endothelium. Low concentrations of PGF2 alpha ranging from 10(-11) to 10(-8) M produced a dose-dependent relaxation in the monkey arteries. PGF2 alpha (10(-7) M) produced a transient contraction followed by a small relaxation, whereas higher concentrations (greater than 10(-6) M) of PGF2 alpha induced only contractions. The PGF2 alpha-induced relaxation was not observed in the canine cerebral arteries. The PGF2 alpha-induced relaxation of the monkey cerebral arteries was not affected by treatment with 10(-7) M propranolol, 10(-7) M atropine, or 10(-6) M cimetidine. In monkey cerebral arteries without endothelium, PGF2 alpha in concentrations ranging from 10(-11) to 10(-6) M caused no relaxation. Treatment with 5 X 10(-5) M aspirin, 3 X 10(-5) M NG-monomethyl-L-arginine, and 10(-5) M oxyhemoglobin significantly suppressed the PGF2 alpha-induced relaxation. These results suggest that low concentrations of PGF2 alpha may produce an endothelium-dependent relaxation in monkey cerebral arteries and that the relaxation may be mediated by release of both endogenous vasodilative prostaglandins and endothelium-derived relaxing factor from endothelial cells.
Hypertrophy alters effect of Ins(1,4,5)P3 on Ca2+ release in skinned rat heart muscle
Authors: Furukawa N. , Bassett A. L. , Furukawa T. , Myerburg R. J. , Kimura S.
Published: December 2017

The effects of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] on the ability of the sarcoplasmic reticulum (SR) to accumulate and release Ca2+ and on the Ca2+ sensitivity of the contractile proteins were investigated using chemically (saponin) skinned cardiac fibers (60–120 microns diam) obtained from normal and pressure-overloaded hypertrophied rat left ventricles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta 3-6 wk before study. Age- and weight-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio by 45%. Ins(1,4,5)P3 at a concentration of 10 microM did not change the Ca(2+)-tension relationship at Ca2+ concentrations of 10(-7) to 10(-5) M in either normal or hypertrophied fibers. Ins(1,4,5)P3 also did not influence Ca2+ uptake by the SR in either normal or hypertrophied fibers. Ins(1,4,5)P3 did not induce Ca2+ release from the SR directly in either group. However, pretreatment with Ins(1,4,5)P3 enhanced the 5 mM caffeine-induced Ca2+ release by 80.5 +/- 22.7% in normal fibers enhances, rather than directly induces, SR Ca2+ release in normal rat hearts and that sustained pressure overload diminishes the response of the SR Ca(2+)-release system to Ins(1,4,5)P3, an action that may be partly responsible for contractile dysfunction in cardiac hypertrophy.
Adenosine attenuation of catecholamine-enhanced contractility of rat heart in vivo
Authors: Romano F. D. , Naimi T. S. , Dobson J. G.
Published: December 2017

The antiadrenergic action of adenosine was examined in open- and closed-chest preparations of anesthetized rats. The positive inotropic effects of a jugular vein infusion of either isoproterenol or epinephrine were attenuated by phenylisopropyladenosine, an adenosine A1-receptor agonist. 1,3-Dipropyl,8-cyclopentylxanthine, a specific A1-receptor antagonist, inhibited the action of phenylisopropyladenosine. The results indicate that adenosine receptor-mediated mechanisms are functional in the blood-perfused rodent heart and support the possibility of a physiological role for adenosine in modulating cardiac contractility.
Flow-induced changes in Ca2+ signaling of vascular endothelial cells: effect of shear stress and ATP
Authors: Mo M. , Eskin S. G. , Schilling W. P.
Published: December 2017

The effect of hemodynamic flow on apparent cytosolic free Ca2+ concentration ([Ca2+]i) of cultured bovine aortic endothelial cells was examined in the absence and presence of adenine nucleotides using microfluorimetric analysis of fura-2 fluorescence. In the absence of adenine nucleotides, flow-induced shear stress produced little change (less than 10 nM) in [Ca2+]i. Similar results were obtained using calf pulmonary artery and human umbilical vein endothelial cells. However, addition of the adenine nucleotides ATP, ADP, or AMP under flow conditions produced a transient peak increase in [Ca2+]i that was followed by a sustained elevation. The rank order of potency for the peak response was ADP greater than or equal to ATP much much greater than AMP. Adenosine was without effect on [Ca2+]i. Washout of ATP resulted in the immediate return of [Ca2+]i to basal values, indicating that the effect of ATP was rapidly reversible. Decreasing the flow rate to zero during the sustained phase also resulted in an immediate decrease of [Ca2+]i. Similar results were obtained with ADP and AMP but not with the nonhydrolyzable adenine nucleotide analogues alpha,beta-methyleneadenosine-5'-diphosphate, beta,gamma-imidoadenosine-5'-triphosphate, or beta,gamma-methyleneadenosine-5'-triphosphate. Furthermore, the rate of [Ca2+]i decrease upon cessation of flow during the sustained phase of the response to ATP was inversely proportional to the ATP concentration. These results suggest that hydrolysis of ATP to adenosine by the ectonucleotidase is responsible for the termination of the ATP response under zero-flow conditions. Evaluation of the dose- and flow-dependent response of the cells to ATP indicates that convective-diffusive transport of ATP may play an important role in regulation of endothelial cell [Ca2+]i in presence of ectonucleotidase activity and could have important consequences for the regulation of blood flow in the vasculature.
Origin of anterior interventricular vein blood in domestic swine
Authors: Bier J. , Sharaf B. , Gewirtz H.
Published: December 2017

This study tested the hypothesis that anterior interventricular vein effluent of domestic swine is composed primarily of blood draining the perfusion territory of the left anterior descending coronary artery. As a corollary, the extent to which circumflex and right coronary inflow contributes to anterior interventricular vein outflow also was determined. Experiments were conducted in vitro with buffer-perfused swine hearts in which anterior interventricular vein flow was measured under various combinations of left anterior descending and circumflex coronary perfusion. Studies also were performed in vivo in different groups of intact swine with normal, stenosed, and occluded left anterior descending coronary artery. The results of the study confirm the hypothesis and demonstrate under a variety of conditions that at least 90% of anterior interventricular vein effluent is derived from blood originating from myocardium perfused by the left anterior descending coronary artery.
Inhibition of transient outward K+ current by DHP Ca2+ antagonists and agonists in rabbit cardiac myocytes
Authors: Gotoh Y. , Imaizumi Y. , Watanabe M. , Shibata E. F. , Clark R. B. , Giles W. R.
Published: December 2017

The 1,4-dihydropyridine (DHP) Ca2+ antagonists and agonists can inhibit a time- and voltage-dependent, but intracellular Ca(2+)-independent transient outward K+ current (It), in myocytes from rabbit atrium. In the presence of 0.3 mM CdCl2, DHPs decreased the peak It slightly and markedly accelerated its apparent rate of inactivation. When the inhibition of It was measured from integrated It records, the 50% inhibitory concentrations (IC50) of nicardipine and BAY K 8644 were 630 nM and 7 microM, respectively, and the IC50 of nicardipine for inhibition of the Ca2+ current (ICa) was only approximately fourfold lower (160 nM). The inhibition of It by nicardipine was not affected by changing holding potential from -55 to -100 mV; in contrast, the inhibitory effect on ICa was significantly reduced by this hyperpolarization. We conclude that the DHP Ca2+ antagonist nicardipine blocks It at similar doses to those that block ICa and that nicardipine blocks this K+ current by mechanism different from that for ICa inhibition. This inhibitory effect on It is shared by other DHP compounds; the rank order for potency of It inhibition is nicardipine greater than benidipine greater than nisoldipine greater than BAY K 8644 greater than nitrendipine greater than nifedipine.
Adenosine receptor blockade with 8-p-sulfophenyltheophylline aggravates coronary constriction
Authors: Martin S. E. , Tidmore W. C. , Patterson R. E.
Published: December 2017

We examined the role of adenosine in modulating the coronary constrictor effect of neuropeptide Y (NPY). Anesthetized dogs (n = 22) were instrumented to record hemodynamics and to collect arterial and coronary venous blood. In control dogs (n = 7), during the first 30 min before NPY, baseline coronary resistance fell slightly. By 10 min after NPY (42 nmol over 4 min), coronary resistance was increased by 30% and fell slowly to pre-NPY levels over the ensuing hour. Intravenous (7.5 mg/kg, n = 3) or intracoronary (to 100 microM arterial concentration, n = 12) infusion of 8-p-sulfophenyltheophylline (8-THEO) blocked the vasodilator effects of adenosine but did not alter the peak dilation seen with papaverine or reactive hyperemia. Over 30 min before NPY, infusion of 8-THEO increased baseline resistance by 31% as it reduced coronary blood flow, despite no change in other hemodynamic parameters or myocardial oxygen consumption. The coronary constrictor effect of NPY was magnified in the presence of adenosine receptor blockade. At 3 min, coronary resistance was increased by 34%, at 5 min by 52%, and at 10 min by 59%. The effect of adenosine receptor blockade on constriction due to NPY could not be attributed to a nonspecific alteration in cardiac function or oxygen consumption. In addition, the increase in baseline coronary resistance following receptor blockade correlated with the worsening of the coronary constriction following NPY (r = 0.48, P less than 0.05). Thus it appears that adenosine modulates an imposed constriction of coronary vessels and acts as a “host defense” to restore coronary tone toward normal.
Exogenous prostacyclin does not sensitize arterial baroreceptors
Authors: Hirooka Y. , Ando S. , Imaizumi T. , Suzuki S. , Takeshita A.
Published: December 2017

It has been shown that prostacyclin (PGI2) sensitizes cardiac receptors. However, the effects of PGI2 on arterial baroreceptors are not well understood. In rabbits anesthetized with alpha-chloralose (n = 12), we examined reflex changes in multiunit efferent renal sympathetic nerve activity (RSNA) during hypotension caused by intravenous PGI2 (0.1, 0.2, 0.5, 1.0, 2.0 micrograms/kg), nitroglycerin (NG; 5, 10, 20, 50, 100 micrograms/kg), and sodium nitroprusside (SNP; 5, 10, 20, 50, 100 micrograms/kg) before and after bilateral vagotomy. Before vagotomy, RSNA increased during hypotension caused by NG or SNP (P less than 0.01) but did not significantly change during comparable hypotension caused by PGI2. After vagotomy, PGI2 increased RSNA as much as NG or SNP. In another group (n = 6), we examined the changes in aortic pressure (AoP), multiunit afferent aortic nerve activity (ANA), and the aortic diameter (AoD) during hypotension caused by intravenous PGI2, NG, and SNP. The relationship between changes in AoP and those in ANA did not differ during hypotension caused by the three drugs. The relationship between changes in AoP and those in AoD and that between changes in AoD and those in ANA also did not differ. Finally, we examined changes in AoP, ANA, and AoD during ramp increases or decreases of AoP caused by intravenous angiotensin II or NG under background infusion of saline, PGI2, or SNP (n = 6). The relationship among these variables did not differ during infusion of PGI2 and SNP. These results suggest that PGI2 stimulates cardiac receptors with vagal afferents but does not sensitize arterial baroreceptors.
Calcium-activated potassium channels from coronary smooth muscle reconstituted in lipid bilayers
Authors: Toro L. , Vaca L. , Stefani E.
Published: December 2017

This work is the initial characterization of Ca(2+)-activated K+ (KCa) channels from coronary smooth muscle reconstituted into lipid bilayers. The channels were obtained from a surface membrane preparation of porcine coronary smooth muscle. KCa channels were the predominant K+ channels in this preparation. The conductance histogram (n = 137 channels) revealed two main populations of “maxi” KCa channels with conductances of 245 and 295 pS. Each population could be subdivided in two “isoforms” or “isochannels” with different functional properties (voltage and Ca2+ sensitivities and kinetics). The analysis of “burst” probability of opening showed that at pCa 4 the two isochannels of 245 pS (KCa-1 and KCa-1') had half-activation potentials (V1/2) of -80 and 6 mV, respectively. The isochannels of 295 pS (KCa-2 and KCa-2') had V1/2 of -28 and -66 mV, respectively. KCa-1 had the highest Ca2+ sensitivity; at -60 mV, the concentration of half-activation value for Ca2+ was 1.2 +/- 0.3 microM (n = 5). External tetraethylammonium reduced channel amplitude in a voltage-dependent manner; dissociation constant was 180 +/- 6 and 466 +/- 41 microM at -40 and +80 mV, respectively (n = 5). Charybdotoxin (5-50 nM) produced typical long closings. These effects were similar in all the channels. We conclude that coronary smooth muscle possesses isoforms of maxi KCa channels with Ca2+ and voltage sensors with different properties, which may confer to each channel a specific functional role.
Alterations in myocardial contractility in conscious dogs with dilated cardiomyopathy
Authors: Shannon R. P. , Komamura K. , Stambler B. S. , Bigaud M. , Manders W. T. , Vatner S. F.
Published: December 2017

We investigated the changes in left ventricular (LV) geometry and myocardial contractility in eight conscious chronically instrumented dogs studied before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. Significant increases (P less than 0.01) were observed in cardiac dimensions in both the LV long and short axes and in end-diastolic volume (control: 53 +/- 1 ml; cardiomyopathy: 76 +/- 2 ml) and end-systolic volume (control: 27 +/- 2 ml; cardiomyopathy: 56 +/- 7 ml). This was associated with the left ventricle assuming a more spherical shape with LV long-to-short axis ratio falling from 1.59 +/- 0.05 to 1.47 +/- 0.04 (P less than 0.05). Both isovolumic (LV dP/dt) and ejection phase indexes (LV mean velocity of circumferential fiber shortening, corrected LV short-axis diameter at point of maximum shortening, and LV ejection fraction) were depressed by 50%. The end-systolic elastance was also depressed significantly (control: 16.6 +/- 0.7 g.cm-2.ml-1; cardiomyopathy: 10.1 +/- 1.7 g.cm-2.ml-1, P less than 0.02). However, cardiac output was maintained at 3 wk due to a compensatory tachycardia (+31 +/- 3 beats/min), plasma volume expansion (+295 +/- 68 ml, P less than 0.05), and greater reliance on the Frank-Starling mechanism. However, in an additional four dogs studied at 4-5 wk, cardiac output fell significantly (P less than 0.05). Thus rapid ventricular pacing results in dilated congestive cardiomyopathy in conscious dogs characterized by globally depressed myocardial systolic function and changes in LV shape.
Rate-induced increase in plasma atrial natriuretic factor can occur independently of changes in atrial wall stretch
Authors: Riddervold F. , Smiseth O. A. , Hall C. , Groves G. , Risoe C.
Published: December 2017

Tachycardia is known to increase the plasma level of atrial natriuretic factor (ANF). The aim of the study was to determine whether such release of ANF can occur independently of increased atrial wall stretch. Seven anesthetized dogs were instrumented with pressure catheters and sonomicrometer crystals to measure left and right auricular and atrial free wall dimensions. During atrial pacing, the measured atrial dimensions were kept constant by adjusting vascular constrictors placed around the great vessel trunks. When atrial rate was increased progressively by pacing at 150, 200, and 250 min-1, plasma ANF increased from 40.8 +/- 5.4 to 43.0 +/- 6.0 (P = NS) and 103.1 +/- 17.6 (SE) pmol/l (P less than 0.05), respectively. Repeating the pacing sequence at two different levels of elevated left atrial pressure caused at each level a similar increase in plasma ANF at 250 min-1. The relationship between plasma ANF and atrial dimensions was shifted upward by pacing, such that ANF was higher for any given atrial dimension. In conclusion, pacing tachycardia elevates plasma ANF in the presence of constant atrial dimensions. These results support the hypothesis that chronotropic stimulation can cause release of ANF by a mechanism that is independent of atrial stretch.
Defibrillation shocks increase myocardial pacing threshold: an intracellular microelectrode study
Authors: Li H. G. , Jones D. L. , Yee R. , Klein G. J.
Published: December 2017

Defibrillation is known to cause inability to pace the heart acutely, but the mechanism is unknown. This study used microelectrode techniques to directly evaluate the effect of defibrillation shocks on the pacing threshold and membrane potentials from superfused guinea pig papillary muscles. Failure of pacing stimuli to induce action potentials (pacing failure) followed shocks of 50-200 V/cm, with pacing failure duration correlated with shock intensity. Increasing pacing strength from one to three times diastolic threshold decreased the incidence and duration of pacing failure. Decreased extracellular calcium concentration and verapamil added to the superfusate increased the duration of pacing failure. Membrane potential depolarization occurred after shock, but pacing failure did not correlate with depolarization magnitude. We conclude that defibrillation shocks directly cause shock intensity-dependent increase of myocardial pacing threshold. The pacing threshold of the myocardium can be increased after defibrillation shock independent of hypoxia or shock-induced depolarization and may involve membrane changes in calcium handling.
Endothelial albumin permeability is shear dependent, time dependent, and reversible
Authors: Jo H. , Dull R. O. , Hollis T. M. , Tarbell J. M.
Published: December 2017

Altered permeability of vascular endothelium to macromolecules may play a role in vascular disease as well as vascular homeostasis. Because the shear stress of flowing blood on the vascular wall is known to influence many endothelial cell properties, an in vitro system to measure transendothelial permeability (Pe) to fluorescein isothiocyanate conjugated bovine serum albumin under defined physiological levels of steady laminar shear stress was developed. Bovine aortic endothelial cells grown on polycarbonate filters pretreated with gelatin and fibronectin constituted the model system. Onset of 1 dyn/cm2 shear stress resulted in a Pe rise from 5.1 +/- 1.3 x 10(-6) cm/s to 21.9 +/- 4.6 X 10(-6) cm/s at 60 min (n = 6); while 10 dyn/cm2 shear stress increased Pe from 4.8 +/- 1.5 X 10(-6) cm/s to 50.2 +/- 6.8 X 10(-6) cm/s at 30 min and 49.6 +/- 8.9 X 10(-6) cm/s at 60 (n = 9). Pe returned to preshear values within 120 and 60 min after removal of 1 and 10 dyn/cm2 shear stress, respectively. The data show that endothelial cell Pe in vitro is acutely sensitive to shear stress.
Atrial dynamics, atrial natriuretic factor, tachycardia, and blood volume in anesthetized rabbits
Authors: King K. A. , Ledsome J. R.
Published: December 2017

The effects of tachycardia and a slow (1%/min) 20% reduction and elevation of blood volume (BV) on right atrial pressure (RAP), right atrial dimension (RAD), and plasma immunoreactive atrial natriuretic factor (IR-ANF) were examined in anesthetized rabbits. Plasma IR-ANF was significantly increased during pacing at 6 Hz in the presence of high BV but not at low BV. Mean RAP increased with expansion of BV, but this change was not associated with significant changes in IR-ANF. There were no statistically significant changes in systolic or diastolic RAD with alterations in BV or with tachycardia. Tachycardia had no effect on left atrial dimension. Diastolic right atrial wall stress (DRAS) and minute DRAS increased with a 20% increase in BV, but changes in BV did not affect systolic right atrial wall stress (SRAS) or minute SRAS. Tachycardia decreased DRAS at high BV and significantly increased SRAS and minute SRAS. The increases in SRAS and minute SRAS were greater during tachycardia at high BV, suggesting that an interaction between BV and tachycardia results in potentiation of SRAS and minute SRAS. The results suggest that systolic RAS is a significant factor in ANF release during tachycardia at high BV.
Contraction and relaxation of rat aorta in response to ATP
Authors: Dominiczak A. F. , Quilley J. , Bohr D. F.
Published: December 2017

Vascular responses to ATP were studied in aortic rings isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Low concentrations of ATP (10 nM to 10 microM) caused relaxation and high concentrations (0.1 mM to 10 mM) caused contraction. Both of these responses were accentuated by factors released from the endothelium. The endothelium-derived relaxing factor (EDRF) was blocked by NG-monomethyl-L-arginine (L-NMMA). This is the first time that it has been reported that ATP causes the release of an endothelium-derived contracting factor (EDCF). Its release was diminished but not completely blocked by cyclooxygenase inhibitors. Assays of muscle bath prostanoid composition indicated that ATP stimulation caused the release of prostaglandins I2 and E2 and thromboxane A2 from intact aortic rings. Evidence is presented that neither endothelin nor superoxide anion contributed to the EDCF. No difference was observed between WKY and SHRSP with regard to either the endothelial contributions to the response, or the direct action on vascular smooth muscle of ATP. High concentrations of ATP achieved intravascularly in hypoxia may cause vasospasm by release of endothelial prostanoids.
LV oxygen consumption and pressure-volume area: role of norepinephrine and verapamil
Authors: Chung N. , Wu X. , Ritman E. L.
Published: December 2017

The effect of norepinephrine or verapamil on the relationship of left ventricular (LV) myocardial oxygen consumption (MVO2) and systolic pressure-volume area (PVA) was investigated in hearts within the never-opened thorax of dogs with blocked baroreceptor reflex. LV chamber volumes and myocardial blood flow were measured using a fast computed tomography scanner. At 10 micrograms/min delivery rate of norepinephrine, MVO2 (mJ.g-1.cycle-1) equals (2.30 +/- 0.48) PVA + (20.60 +/- 4.24) (n = 11; 1 mJ.g-1.cycle-1 is equivalent to 0.563 ml O2.100 g-1.min-1 at 112 beats/min). With verapamil infusion, MVO2 equals (2.57 +/- 1.33)PVA + (10.73 +/- 3.16) (n = 17). The regression slopes did not differ (P greater than 0.25) for any of the conditions. At comparable PVA values the norepinephrine group showed an increase of MVO2 compared with the prenorephrine baseline state (P less than 0.01), and the verapamil group showed a reduction of MVO2 compared with the preverapamil baseline state (P less than 0.05). We conclude that the MVO2 to LVPVA relationship in the in situ heart, within the never-opened thorax, conveys that the oxygen-wasting effect of catecholamines is quantifiable using the shift in this relationship.
NMR studies of beta-oxidation and short-chain fatty acid metabolism during recovery of reperfused hearts
Authors: Lewandowski E. D. , Chari M. V. , Roberts R. , Johnston D. L.
Published: December 2017

The effects of beta-oxidation on the contractile recovery and metabolic activity of postischemic (10 min) rabbit hearts were examined during reperfusion with the short-chain fatty acid butyrate. Hearts received either 13C-enriched butyrate or acetate to evaluate metabolic targeting with 13C nuclear magnetic resonance (NMR) spectroscopy. Acetate and butyrate supported similar contractility (rate of pressure development, dP/dt) and 31P-NMR-detected, high-energy phosphate (HEP) levels during normal perfusion. In postischemic hearts, butyrate sustained a greater percentage of preischemic dP/dt (83 +/- 4%) than did acetate reperfusion (44 +/- 6%, P less than 0.05) with no differences in HEP. The efficiency of oxygen consumption per unit of work was greater in hearts reperfused with butyrate (2.8 +/- 0.2 microM.g-1.mmHg-1) vs. acetate (3.4 +/- 0.1). Inhibition of butyrate oxidation with 4-bromocrotonic acid (4-BCA) during normal perfusion severely reduced dP/dt and HEP. Acetate supported normal dP/dt and HEP levels during perfusion with 4-BCA and butyrate, but contractile recovery during reperfusion with acetate, 4-BCA, and butyrate (46 +/- 6%) was similar to that with acetate alone. With acetate and butyrate combined at reperfusion, acetate accounted for 56% of substrate entering oxidative metabolism at acetyl CoA and delayed contractile recovery (57 +/- 5% at midpoint and 80 +/- 6% at end). Thus improved respiratory efficiency of contraction in reperfused hearts was related to the activity of beta-oxidation.
Different effects of intracellular Ca and protein kinase C on cardiac T and L Ca currents
Authors: Tseng G. N. , Boyden P. A.
Published: December 2017

We studied the effects of changing the intracellular Ca level ([Ca]i) and activating protein kinase C on the cardiac T and L Ca channels in single canine ventricular and Purkinje cells. Lowering [Ca]i increased the L current but decreased the T current, whereas elevating [Ca]i caused opposite changes. In ventricular cells, isoproterenol (1 microM) increased the amplitude of not only the L but also the T currents; the latter effect probably was secondary to a rise in [Ca]i following the augmentation of the L current. 12-O-tetradecanoylphorbol-13-acetate (TPA, 100 nM) decreased the T current but first increased and then decreased the L current. The TPA effects on the T and L currents were not mimicked by a phorbol ester that does not activate PKC (4 alpha-phorbol 12,13-didecanoate) and were prevented by a protein kinase inhibitor (H-8), confirming the involvement of PKC activity in these modulatory processes. We conclude that elevating [Ca]i and activating PKC have opposite effects on the T and L Ca currents in canine cardiac cells. The extent and time course of the changes in these two intracellular messengers will most likely determine the effects on the two cardiac Ca currents of neurotransmitters and hormones that can activate phospholipase C.
Prevention of the oxygen paradox in hypoxic-reoxygenated hearts
Authors: Schluter K. D. , Schwartz P. , Siegmund B. , Piper H. M.
Published: December 2017

Reoxygenation after 60 min substrate-free hypoxic perfusion (modified Tyrode solution, 37 degrees C) caused isolated Langendorff hearts (from rats) to rapidly develop hypercontracture and sarcolemmal disruptions indicated by massive and sudden loss of enzymes ("oxygen paradox"). Reoxygenation (30 min) caused an augmented loss of creatine kinase by 25.8% (lactate dehydrogenase by 40.1%) of the initial total tissue activity. It was investigated whether a temporary contractile blockade by 2,3-butanedione monoxime (BDM; 20 mM) can prevent reoxygenation-induced injury. In the presence of BDM, reoxygenation no longer caused hypercontracture or increased enzyme release. Instead, ultrastructure recovered, and contents of creatine phosphate (CrP) were partially restored (60 min hypoxia: 0.4 mumol CrP/g dry wt; after subsequent 60 min reoxygenation in presence of BDM: 7.8 mumol CrP/g dry wt). When BDM was eluted after first 20 min of reoxygenation, an attenuated but distinct increase in enzyme release was still observed. When BDM was eluted after 60 min of reoxygenation, ultrastructure did not deteriorate and increase of enzyme release remained virtually absent. During first 30 min after removal of BDM, the increased loss of creatine kinase amounted to only 5.7% (lactate dehydrogenase to 6.9%) of the initial total tissue activity. The results demonstrate that the oxygen paradox can be prevented in the hypoxic-reoxygenated heart when the contractile apparatus is temporarily paralyzed during the initial phase of reoxygenation.
Effect of membrane potential on H1-receptor-mediated 45Ca influx in coronary artery
Authors: Khoyi M. A. , Bowen S. M. , Keef K. D.
Published: December 2017

These studies were undertaken to determine whether agonist-induced 45Ca influx in the coronary artery is modified under conditions in which Na+ pump activity (and consequently membrane potential) is altered. 45Ca influx and contraction were measured in the rabbit coronary artery with the H1-receptor agonist 2-(2-aminoethyl)pyridine (AEP, 10(-4) M) after prolonged Na+ pump block (leading to profound depolarization) and after enhanced Na+ pump activity (leading to hyperpolarization). AEP contracted vessels, enhanced 45Ca influx into the smooth muscle, and increased 45Ca efflux. The AEP-induced contraction was reduced but not abolished with either nifedipine (10(-6) M) or Ca(2+)-free solution. In tissues subjected to prolonged Na+ pump block AEP caused contraction but 45Ca influx was not increased over the unstimulated tissue. Ca(2+)-free solution and nifedipine reduced but did not abolish these contractions. In tissues with enhanced Na+ pump activity AEP caused contraction but 45Ca influx was not increased. Ca(2+)-free solution reduced these contractions but nifedipine did not. We conclude that the measurable 45Ca influx changes in a manner that is compatible with the characteristics of voltage-gated Ca2+ channels that have a low open probability during hyperpolarization and are inactivated by a period of long slow depolarization.
A simple and sensitive bioassay method for detection of EDRF with RFL-6 rat lung fibroblasts
Authors: Ishii K. , Sheng H. , Warner T. D. , Forstermann U. , Murad F.
Published: December 2017

Detailed characteristics of a new bioassay method for detection and quantification of endothelium-derived relaxing factor (EDRF) are described. Guanosine 3',5'-cyclic monophosphate (cGMP) responses of RFL-6 rat fetal lung fibroblast cells were utilized to estimate the activity of nitric oxide (NO) and EDRF. The conditioned medium from bovine aortic endothelial (BAE) cells cultured in tissue culture plates was quickly transferred to RFL-6 incubations to determine EDRF. In the presence of superoxide dismutase, RFL-6 cells cultured in six-well tissue culture plates exhibited very high sensitivities to both NO and EDRF; e.g., they responded to NO at a concentration as low as 2 nM and the basal release of EDRF from 1-2 X 10(6) BAE cells. Based on the lower detection limit of the radioimmunoassay for cGMP, calculations reveal that 100-200 fmol of NO and the basal EDRF release from 1-2 X 10(5) BAE cells can be detected with RFL-6 cells by choosing smaller culture wells. Thus this method is more sensitive than any other currently available. Furthermore, it may be widely used, since the instrumentation required is presently available in many laboratories. This bioassay technique for EDRF and NO is sensitive, simple, and quite useful for the evaluation of experimental conditions and compounds that regulate EDRF release from various endothelial cells and tissues.
Cytochrome P-450-dependent vasodilation of rat kidney by arachidonic acid
Authors: Oyekan A. O. , McGiff J. C. , Quilley J.
Published: December 2017

Our previous studies indicated a role for cytochrome P-450-dependent enzymes in generating the mediators of the vasodilator effect of arachidonic acid (AA) in the preconstricted indomethacin-treated perfused kidney of the rat. We report that in vivo induction of cytochrome P-450 enzymes with 3-methylcholanthrene-beta-naphthoflavone or dexamethasone enhanced the renal vasodilator effect of AA in this experimental preparation. Conversely, depletion of cytochrome P-450 enzymes with stannous chloride or cobalt chloride diminished the vasodilator response to AA. Injection of AA resulted in the release of relaxant material into the renal effluent detected by superfusion of rabbit aortic rings. Inhibition of cytochrome P-450 with 7-ethoxyresorufin reduced the release of vasorelaxant material. Metabolism of labeled AA by the kidney revealed four peaks of radioactivity that were recovered from the renal effluent. The heights of these peaks were reduced by 7-ethoxyresorufin. These results provide further evidence for cytochrome P-450-dependent metabolism of AA to one or more vasodilator products by the rat kidney.
Hemodynamic effects of posterior hypothalamic injection of neuropeptide Y in awake rats
Authors: Martin J. R. , Knuepfer M. M. , Westfall T. C.
Published: December 2017

Unilateral microinjection of neuropeptide Y (NPY) into the posterior hypothalamic nucleus was previously found to evoke a sympathoexcitatory-mediated increase in mean arterial pressure (MAP) in urethan-anesthetized rats. In this study, the effect of unilateral injection of NPY into the posterior hypothalamic nucleus on the cardiovascular system of conscious, freely moving rats was determined. Microinjection of NPY (0.2-2.4 nmol) or the cholinergic agonist carbachol (0.5-5.5 nmol) resulted in concentration-dependent increases in MAP. Pretreatment of animals with 7.5 mg/kg iv of the ganglionic blocker pentolinium resulted in a blockade of the increase in MAP evoked by microinjection of NPY (2.4 nmol) or carbachol (3.3 nmol). Despite their similarity of effects on MAP, NPY and carbachol evoked different changes in heart rate. NPY increased heart rate, whereas carbachol evoked a biphasic change in heart rate that consisted of an initial increase followed by a decrease. In addition, carbachol caused increases in both hindquarter and mesenteric vascular resistances, whereas NPY caused a short-lasting increase in mesenteric resistance and a tendency toward an increase in hindquarter resistance. Both NPY and carbachol increased total peripheral resistance while NPY decreased stroke volume. Cardiac output was not significantly affected by either NPY or carbachol, although NPY had a tendency to decrease cardiac output. These results suggest that microinjection of NPY or carbachol into the posterior hypothalamic nucleus of conscious rats evokes an increase in MAP primarily as a result of sympathoexcitation and that NPY and carbachol selectively affect autonomic nervous system control of the cardiovascular system.
Interstitial adenosine concentration during norepinephrine infusion in isolated guinea pig hearts
Authors: Gorman M. W. , Wangler R. D. , Bassingthwaighte J. B. , Mohrman D. E. , Wang C. Y. , Sparks H. V.
Published: December 2017

This study determined the effect of norepinephrine (NE) on cardiac interstitial fluid adenosine concentration [( ADO]isf). Isolated guinea pig hearts were perfused with a Krebs-Henseleit buffer solution. Radiolabeled albumin, sucrose, and adenosine were injected under control conditions and after 3 and 20 min of NE infusion to obtain multiple indicator dilution curves that were used to determine capillary transport parameters for adenosine. These parameters together with venous adenosine concentrations were used in a mathematical model to a calculate [ADO]isf. Capillary transport parameters were not changed significantly by NE infusion. Because of uncertainty regarding two model parameters, two sets of [ADO]isf values were calculated. One set used best-fit values obtained from indicator dilution curves, and a second set used parameters chosen to provide the highest [ADO]isf values consistent with indicator dilution curves. Venous adenosine concentrations were 1.9 +/- 0.4 nM under control conditions and 243 +/- 110 and 45 +/- 25 nM after 3 and 20 min of NE infusion, respectively. Calculated [ADO]isf was 2.6-9.4, 591-1,288, and 166-324 nM, respectively, under these same conditions. We conclude that NE infusion greatly increases [ADO]isf, and adenosine is responsible for most of the vasodilation at 3 min. The subsequent fall in venous concentration is due to a fall in [ADO]isf rather than to decreased capillary permeability. Vascular resistance remained low while [ADO]isf fell, which suggests that additional vasodilators are important during maintained NE infusion.