bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial infarct size and ventricular function in rats.
Authors: Pfeffer M A , Pfeffer J M , Fishbein M C , Fletcher P J , Spadaro J , Kloner R A , Braunwald E
Published: June 2012

To define the relationship between infarct size and ventricular performance, we performed hemodynamic studies in rats 21 days after left coronary artery occlusion. Ventricular performance was assessed under ether anesthesia by measurements of baseline hemodynamics and stressed performance as determined by the peak cardiac output and stroke volume obtained during intravenous volume loading and by the peak left ventricular developed pressure obtained during occlusion of the ascending aorta. Infarct size was determined by planimetry of the endocardial circumference of each of four histological slices of the left ventricle. Rats with small (4-30%) myocardial infarctions had no discernible impairment in either baseline hemodynamics or peak indices of pumping and pressure-generating ability when compared to the sham-operated, noninfarcted rats. Rats with moderate (31-46%) infarctions had normal baseline hemodynamics but reduced peak flow indices and developed pressure. Rats with infarctions greater than 46% had congestive heart failure, with elevated filling pressures, reduced cardiac output, and a minimal capacity to respond to pre- and after load stresses. The entire spectrum of postinfarction ventricular function was observed, from no detectable impairment to congestive failure. In this model of histologically healed myocardial infarction, the impairment of left ventricular function was directly related to the loss of myocardium.
Direct evidence for the presence of a different converting enzyme in the hamster cheek pouch.
Authors: Cornish K G , Joyner W L , Gilmore J P
Published: June 2012

Kininase II (angiotensin I-converting enzyme) is generally accepted to be the enzyme responsible for the conversion of angiotensin I (A I) to angiotensin II (A II). This study examined the response of the microvasculature of the hamster cheek pouch to the local application of A I, A II, and the renin substrate, tetradecapeptide (TDP). A I and TDP caused a localized vasoconstriction that was not blocked by converting enzyme inhibitors (CEI: BPF5a for A I and BPF5a and the nonapeptide inhibitor for TDP). However, both the A II antagonist [Sar1, Ala8]angiotensin II and the antiserum to A II blocked completely the A I- and TDP-induced vasoconstriction. Sixty-eight percent of the applied A I was converted to A II in the presence of CEI as well as in its absence. It is concluded that the vasculature of the hamster cheek pouch converts significant amounts of A I to A II by a route that does not involve kininase II.
Renin secretion in the chronically perfused pulseless calf. Evidence for failure of stimulation by decreased pulse pressure.
Authors: Shoor P M , Marzec U M , Griffith L D , Hammill F S , Dilley R B , Bernstein E F
Published: June 2012

To study the influence of arterial pulse pressure on renin release, a chronic pulseless calf preparation was developed using a centrifugal left ventricular bypass blood pump. After pump implantation and recovery, control measurements of renal vein and arterial plasma renin activity, arterial pressure, and renal artery flow were obtained. The centrifugal bypass pump rate then was increased to capture cardiac output completely, and nine conscious calves were perfused in a nonpulsatile manner (pulse pressure less than 5-10 mm Hg) for 48 hours. Nonpulsatile perfusion was well tolerated and serum sodium, potassium, creatinine, and blood urea nitrogen were unchanged during bypass. Mean arterial pressure remained relatively constant [114 +/- 3 (SE) mm Hg] during bypass, and was not significantly changed from control. Although renal blood flow decreased slightly from control (667 +/- 84 ml/min) during the nonpulsatile perfusion period (555 +/- 73 ml/min), renin secretion did not increase significantly from control (482 +/- 81 ng angiotensin I/ml per hr per min) during the bypass period (531 +/- 99). A diurnal cycle of renin secretin was observed during the pulseless perfusions. These data document the lack of any significant stimulatory influence of decreased pulse pressure on renin secretion in a chronic awake calf model.
Electrophysiological study of the action of angiotensin II on the rat myometrium.
Authors: Hamon G , Worcel M
Published: June 2012

Angiotensin II (A II) produces a contraction of visceral and vascular smooth muscles of different species. The accompanying electrophysiological changes were measured on strips of rat myometrium at 35 degrees C using the double sucrose-gap technique. A II at concentrations from 5 x 10(-10) to 10(-6)M produces a depolarization and an increase in membrane conductance. This increase in membrane conductance is not membrane potential dependent since it is observed even when the membrane potential is maintained at the resting level. When all Na + in the test solution is replaced by either Li + or Mg (2+), the depolarizing effect of 10(-6)M A II is either markedly reduced or abolished. Under these conditions, A II produces a small initial hyperpolarization, which is modified by external potassium concentration changes and abolished by tetraethylammonium chloride. When all Cl- is replaced by either NO (-3) or cyclohexanesulfamate, A II (10(-6) M) still produces a 20-m V depolarization. The removal of extracellular Ca (2+) or K+ does not have any effect on the depolarizing action of A II, which also is not changed by 10(-3) M ouabain. In conclusion, A II produces a depolarization of the uterine smooth muscle membrane through an increase in the membrane conductance to Na+. The membrane conductance to potassium is increased simultaneously. The contraction induced by A II shows two components: a phasic component triggered by the Ca (2+) entry associated with spike production and a tonic component due to the release of Ca(2+) from intracellular stores.
Unique resistance to guanethidine-induced chemical sympathectomy of spontaneously hypertensive rats: a resistance overcome by treatment with antibody to nerve growth factor.
Authors: Johnson E M , Macia R A
Published: June 2012

The chronic administration of high doses of guanethidine to rats produces complete destruction of the peripheral sympathetic nervous system. In a study of the effect of guanethidine-induced sympathectomy on the development of hypertension is spontaneous hypertensive rats (SHR, Okomoto strain), only a partial sympathectomy could be produced as assessed by biochemical parameters (tyrosine hydroxylase activity in ganglia and tissue norepinephrine concentrations) and by evaluation of response to stimulation of vasomotor outflow in pithed rat preparations. Other strains of rats (Sprague-Dawley, American Wistar, Kyoto Wistar) were uniformly sensitive to guanethidine sympathectomy. The resistance to guanethidine was not due to a lower accumulation of guanethidine in the neurons of SHR. Addition to the guanethidine treatment of low doses of antibody to nerve growth factor (NGF), which itself produced only a modest sympathectomy, resulted in an almost complete sympathectomy. SHR did not become hypertensive when sympathectomized by combined guanethidine-anti NGF. These results show that the sympathetic neurons of SHR differ from those of other strains with respect to sensitivity to guanethidine cytotoxicity and suggest the possibility of a role for NGF in that altered responsiveness.
Age-related cardiovascular effects of catecholamines in anesthetized piglets.
Authors: Buckley N M , Gootman P M , Yellin E L , Brazeau P
Published: June 2012

We studied cardiac and peripheral circulatory effects of graded doses of catecholamines (0.05-1.0 microgram/kg) in piglets aged less than or equal to 1 day, 2--4 days, 1 wweek, 2 weeks, and 2.5-3 months, under anesthesia with pentobarbital. We evaluated cardiovascular function from simultaneous recordings of aortic pressure, ventricular pressure and its first derivative, heart rate, and phasic carotid and femoral blood flows. We calculated vascular resistance as the ratio of mean aortic pressure to mean flow. The age of onset of a given cardiovascular response was determined, and magnitudes of each type of response were compared among the age groups. Norepinephrine elevated the blood pressure at all doses in piglets of all ages, elicited reflex bradycardia only in older piglets, and increased carotid resistance. Epinephrine elevated the blood pressure at all doses in piglets less than 1 week old, but low doses lowered the blood pressure in piglets older than 1 week of age; resistance changes in the femoral and carotid circulations were variable except in the 2.5-3 month age group. Isoproterenol increased cardiac contractility at all doses in piglets of all ages and increased heart rate at low doses in piglets older than 2 days of age; however, blood pressure and femoral resistance decreases were age and dose dependent. There were age-related differences in the catecholamine dose required to elicit a given cardiac or peripheral circulatory effect and age-related differences in the direction and magnitude of such effects. These results provide evidence for differing rates of postnatal maturation of cardiovascular alpha- and beta- adrenergic mechanisms in swine.
Decreased myocardial contractility in papillary muscles from atherosclerotic rabbits.
Authors: Peterson D W , Griffith D W , Napolitano C A
Published: June 2012

To determine the effect atherosclerosis has on myocardial contractility, we studied the contractile properties of right ventricular papillary muscles from 34 atherosclerotic and 17 control rabbits. We produced atherosclerosis by feeding for 2 to 8 months a diet of 5% lard, 5% peanut oil, 0.5% cholesterol, and 89.5% rabbit pellets. The controls received only rabbit pellets during the same time interval. Contracting isometrically 12 times per minute at 25 degrees C, muscles from the atherosclerotic rabbits developed tension at a lower maximum rate (max dT/dt), had a longer latency, and required longer to develop tension at the maximum rate and to develop peak tension. In isotonic contractions, they shortened with lower maximum velocities and required longer to accelerate to maximum velocity and to shorten maximally. We found no evidence that developed tension or distance shortened differed between the two groups of muscles. Raising the contraction frequency to 24 contractions per minute between the two groups of muscles. Raising the contraction frequency to 24 contractions per minute brought performance of the two groups of muscles closer in both types of contraction. Norepinephrine (1.5 x 10-5 M) nearly abolished differences between performance of the two groups. The loss of contractility correlates poorly with coronary and aortic atherosclerosis. It occurred early in the feeding of the atherogenic diet. We think it was due to a lipid-induced defect in the cardiac cell's handling of calcium.
Evidence from bioassay studies indicating a role for adenosine in cardiac ischemic and hypoxic dilation in the dog.
Authors: Scott J B , Chen W T , Swindall B T , Dabney J M , Haddy F J
Published: June 2012

Previous studies using bioassay demonstrated the presence of a vasoactive substance or substances in coronary sinus blood during myocardial reactive hyperemia which had, on bioassay, characteristics of adenosine and/or AMP. In the present studies, specific blockers were applied to an improved bioassay system to define more precisely the nature of the substance or substances and to determine whether it also appears during local cardiac hypoxia. In the anesthetized dog, coronary sinus blood was bioassayed in an isolated autologous kidney during reactive and hypoxic dilation. During reactive dilation, the bioassay kidney responded with a large resistance increase which was blocked by theophylline and adenosine deaminase and converted to a decrease by adenosine autoblockade. The same was true for hypoxic dilation, except in this instance, only adenosine deaminase reduced the response (40%). Theophylline and adenosine autoblockade eliminated responses of the bioassay organ to both exogenous adenosine and exogenous AMP, but adenosine deaminase was specific for adenosine. These results confirm that one or more vasoactive substances appear in sinus blood in vasoactive quantities during cardiac reactive dilation, and that the peak concentration correlates roughly with the peak flow. In addition, they show that this also is the case for hypoxic dilation. More importantly, they demonstrate that the substance almost certainly is adenosine in the case of reactive dilation, and that increased adenosine levels also are present during hypoxic dilation, but in addition, suggest that AMP sometimes appears in coronary sinus blood during severe cardiac hypoxia in the dog heart.
Continuous positive-pressure ventilation decreases right and left ventricular end-diastolic volumes in the dog.
Authors: Fewell J E , Abendschein D R , Carlson C J , Murray J F , Rapaport E
Published: June 2012

We investigated the mechanism(s) responsible for the decreased cardiac output during continuous positive-pressure ventilation (CPPV). Seven dogs were anesthetized with chloralose-urethane, intubated, and ventilated using a volume ventilator. We measured heart rate, stroke volume, and the determinants of stroke volume: left and right ventricular end-diastolic volumes, isovolumic and ejection phase indices of myocardial contractility, and pulmonary and systemic arterial pressures. Myocardial blood flow was estimated using radioactive microspheres. Variables were measured during a control period of intermittent positive-pressure ventilation (IPPV), 8-20 minutes after the initiation of CPPV using 12 cm H2O positive end-expiratory pressure (PEEP), and 8-20 minutes after the removal of PEEP. CPPV decreased cardiac output but did not affect total or regional myocardial blood flow or the ratio of subendocardial to subepicardial blood flow. Isovolumic and ejection phase indices of myocardial cointractility, heart rate, and systemic arterial pressure did not change during CPPV. Right and left ventricular end-diastolic and end-systolic volumes decreased markedly during CPPV. We conclude that CPPV decreases cardiac output in accordance with Starling's law by decreasing preload.
Effects of rapid stimulation on the transmembrane action potentials of rabbit sinus node pacemaker cells.
Authors: Kodama I , Goto J , Ando S , Toyama J , Yamada K
Published: June 2012

We studied the mechanism of post-overdrive suppression in superfused rabbit sinus node pacemaker cells. Small specimens of sinus node tissue isolated from rabbit hearts were driven at a fast rate (overdrive) for 10-120 seconds using single sucrose gap methods. During the control perfusion (35 degrees C Tyrode's solution), overdrive caused a progressive decrease in maximum diastolic potential (MDP), overshoot (OS), and maximum rate of depolarization at phase 0 [dV/dt)max]. After cessation of the overdrive, the rate of diastolic depolarization decreased, and the spontaneous activity was suppressed temporarily (post-overdrive suppression). MDP, OS, (dV/dt)max, and the spontaneous activity returned within a few seconds to the level observed before overdrive. Atropine (2 x 10(-6) g/ml) did not influence the effects of overdrive. After ouabain administration (3 x 10(-7) g/ml) or in low temperature perfusate (25 degrees C), the effects of overdrive were accentuated, and a marked suppression of spontaneous activity with a long pause of over several seconds was seen following the overdrive. These results suggest that the post-overdrive suppression of sinus node is attributable, at least in part, to ionic shifts following overdrive, and may be potentiated by metabolic dysfunction of pacemaker cells.
Effect of exogenous angiotensin II on renal hemodynamics in the awake rat. Measurement of afferent arteriolar diameter by the microsphere method.
Authors: Hsu C H , Kurtz T W , Slavicek J M
Published: June 2012

We measured cardiac output (CO), renal blood flow (RBF), renal plasma flow (RPF), and afferent arteriolar diameter by the microsphere method, and inulin clearance (GFR) simultaneously in awake rats given an infusion of exogenous angiotensin II (100 ng/min per kg). Angiotensin II did not affect the CO, whereas both RBF and RPF decreased significantly in rats infused with angiotensin II (RBF, 2.88 +/- 0.11, mean +/- SE; RPF, 1.78 +/- 0.09, n = 6) when compared to control animals given saline (RBF, 4.58 +/- 0.31; RPF, 2.80 +/- 0.24 ml/min per 100 g, n = 6, both P less than 0.005, respectively). Both mean arterial pressure (MAP) and renal vascular resistance (RVR) were significantly higher in rats infused with antiogensin II than in controls. The decrease in GFR did not parallel the reduction of RPF in rats infused with angiotensin II as reflected by their higher values of mean filtration fraction (41.1 +/- 1.6%, n = 6) than that of controls (33.7 +/- 2.4%, n = 6, P less than 0.05). Despite significant elevations of MAP and RVR in rats infused with angiotensin II, their mean afferent arteriolar diameter (19.6 +/- 0.24 micron) was not different from that of controls (20.1 +/- 0.39 micron). We conclude that angiotensin II preferentially acts at the site of postglomerular vasculature but not at the afferent arteriole.
Hypoxic contraction of isolated canine coronary artery. Mediation by potassium-dependent exocytosis of norepinephrine.
Authors: Borda L J , Shuchleib R , Henry P D
Published: June 2012

Effects of hypoxia on arterial tone, efflux of potassium, and efflux of norepinephrine were monitored for isolated canine coronary arteries labeled with radioactive potassium (42K) and norepinephrine (3HNE). Hypoxia elicited transient relaxation and subsequent sustained contraction accompanied by marked increases in the effluxes of 42K and 3HNE. After sympathetic nerve injury with 6-hydroxydopamine or cold storage, arteries responded to hypoxia with sustained relaxation. Sustained relaxation occurred also after pretreatment with L-propranolol, but not with D-propranolol or phentolamine. Inhibition of hypoxic contraction by L-propranolol did not alter 42K or 3HNE efflux. Colchicine, an inhibitor of the exocytosis of NE, suppressed hypoxic 3HNE efflux and contraction, but not 42K efflux. Proadifen inhibited 42K and 3HNE efflux as well as contraction. During proadifen-inhibited 42K efflux, exogenous K+ augmented overflow of 3HNE, indicating that proadifen relaxed the hypoxic artery primarily by inhibiting K+-dependent exocytosis of NE. The ratio of NE to dopamine beta-hydroxylase activity was similar in effluents from oxygenated arteries exposed to elevated K+ concentrations and in effluents from hypoxic arteries. Thus, hypoxia evoked exocytotic release of norepinephrine which promoted contraction by a beta-adrenergic mechanism.
The normal human magnetocardiogram. II. A multipole analysis.
Authors: Karp P J , Katila T E , Saarinen M , Siltanen P , Varpula T T
Published: June 2012

This paper presents a multipole analysis of the QRS complex of the normal magnetocardiogram (MCG) of six normal subjects. The multipole strengths up to the octupole term were determined from the measured distribution of the z-component of the cardiac magnetic field (the component perpendicular to the frontal plane). This equivalent magnetic multipole generator was found to represent the cardiac magnetic field with a minimum error of less than 10%. The dipolar term of the expansion was found to represent the field distribution with reasonable accuracy early during ventricular activation, whereas late during activation, the higher multipole terms were clearly more significant.
Effects of indomethacin and meclofenamate on renin release and renal hemodynamic function during chronic sodium depletion in conscious dogs.
Authors: De Forrest J M , Davis J O , Freeman R H , Seymour A A , Rowe B P , Williams G M , Davis T P
Published: June 2012

We studied the control of renin release and renal hemodynamic function by administering prostaglandin synthetase inhibitors to conscious sodium-depleted dogs with blockade of the adrenergic nervous system induced by bilateral renal denervation and propranolol administration. Indomethacin (10 mg/kg) reduced plasma renin activity (PRA) by 59% from a high sodium-depleted value, but PRA was still 3 times the normal sodium-repleted level. Arterial pressure, CCr, CPAH, urine flow, and potassium excretion fell strikingly. Similar results were obtained with meclofenamate. When SQ 14,225 was given to another group of conscious, sodium-depleted dogs with adrenergic nervous system blockade, PRA increased from the high sodium-depleted level of 5.7 to 29.3 ng of Angiotensin I (AI)/ml per hour; indomethacin (10 mg/kg) appeared to reduce PRA (0.05 less than P less than 0.1) but to only 12.1 ng of AI/ ml per hour, which is 17 times the normal level. This high level of PRA after blockade of the adrenergic nervous system and injection of indomethacin suggests that important mechanisms other than norepinephrine and renal prostaglandins control renin release; it is proposed that both the renal vascular receptor and the macula densa are involved. The marked decreases in CCr and CPAH in response to indomethacin emphasize the important role of renal prostaglandins in the control of renal hemodynamic function during sodium depletion.
Inhibition of glycolysis in the denervated dog heart.
Authors: Drake A J , Papadoyannis D E , Butcher R G , Stubbs J , Noble M I
Published: June 2012

We measured glucose metabolism in five dogs before and 3 weeks after cardiac denervation; after this time myocardial norepinephrine is depleted. The discharge by the myocardium, of 14CO2 from infused 14C-D-glucose (U), decreased following denervation (P = 0.05). The ratio of 14CO2 to total CO2 production, which measured the proportion of glucose to total substrate oxidized, also decreased following denervation (P = 0.05). The inhibition of glucose oxidation by denervation was not due to an increase in arterial lactate concentration. There was an associated increase in myocardial content of fructose-6-phosphate in an additional seven dogs (P < 0.01). We postulate that myocardial tissue norepinephrine is one of the controllers of the activity of phosphofructokinase.
Computer simulation of arrhythmias in a network of coupled excitable elements.
Authors: van Capelle F J , Durrer D
Published: June 2012

Arrhythmias were simulated in sheets or cables, consisting of coupled excitable elements, which were characterized by a simple regenerative mechanism. The geometry of the network, the amount of coupling among individual elements, and the properties of the elements relating to excitability, automaticity, and duration of the refractory period could be adjusted arbitrarily in an interactive computer program. When a critical amount of coupling was present between automatic and non-automatic cells, sustained repetitive activity could be initiated and stopped by stimulation of the elements. Using this mechanism, it also was possible to evoke reciprocal activity in a one-dimensional cable. In uniform sheets of coupled elements, circus movement of the activation front could be evoked. The presence of an obstacle or dispersion of the refractory periods of the elements was not a prerequisite for the initiation of circus movements. The vortex of circus movements in the homogeneous sheets consisted of elements which were inactivated by depolarizing currents from the circulating wavefront. In sheets of sufficient size, multiple vortices could be present.
Cardiovascular response to static exercise during selective autonomic blockade in the conscious cat.
Authors: Diepstra G , Gonyea W , Mitchell J H
Published: June 2012

Selective autonomic blockade with propranolol, atropine, and combined atropine and propranolol was used to elucidate the role of the autonomic nervous system in the cardiovascular responses that occur during voluntary static exercise in conscious cats. Seven animals were operantly conditioned to hold a bar against a fixed resistance for a constant time of 15 seconds and were then placed on an exercise regimen which consisted of small weekly increments in resistance. With a resistance of 100 g. heart rate (HR) increased by 7%. With exercise at a resistance of 200 g, HR (10%), left ventricle systolic pressure (LVSP, 16%), and LV max dp/dt (18%) increased, and significant changes in these parameters persisted throughout the remainder of the training period. beta-Adrenergic receptor blockade with propranolol abolished the increase in LV max dp/dt, whereas HR and LVSP increased. After atropine, the increase in HR was abolished at the early training stages, whereas LVSP and LV max dp/dt increased. Administration of atropine and propranolol blocked the increase in HR and LV max dp/dt responses, whereas LVSP increased. In this study, the increased HR in response to exercise was mediated primarily by the parasympathetic nervous system, whereas the increases in LV max dp/dt were mediated by the sympathetic nervous system. Furthermore, the bradycardia accompanying chronic performance of isometric exercise resulted from both an increase in vagal tone and a decrease in sympathetic tone.
Effects of intravenously infused histamine on canine forelimb transvascular protein efflux following adrenergic receptor blockade.
Authors: Grega G J , Marciniak D L , Jandhyala B S , Raymond R M
Published: June 2012

The intravenous infusion of high doses of histamine (400 micrograms base/min) produced only small increases in weight (approximately equal to +30 g) and lymph total protein concentration (+ 0.9 g/100 ml) in canine forelimbs perfused at constant inflow. The weight gain was associated with profound decreases in aortic pressure (112 to 30 mm Hg) and in forelimb perfusion pressure (105 to 75 mm Hg) and marked increases in forelimb skin small-vein pressure (from 12 to 25 mm Hg). After treatment with phentolamine, the intravenous infusion of these doses of histamine under the same conditions produced marked decreases in forelimb perfusion pressure (120 to 60 mm Hg) and failed to increase forelimb skin small-vein pressure, yet still produced only minimal increases in weight (+ 12 g) and lymph total protein concentration (+ 0.8 g/100 ml). Following treatment with both phentolamine and propranolol, the intravenous infusion of histamine caused very marked increases in forelimb weight (approximately equal to +75 g) and lymph total protein concentration (+ 2.9 g/100 ml). These marked increases in forelimb weight and lymph formation were associated with profound decreases in perfusion pressure (112 to 60 mm Hg) but no change in skin small-vein pressure relative to control. These same increases in weight and lymph total protein concentration were observed after treatment with propranolol alone. Thus, treatment with propranolol markedly increased net fluid filtration and protein efflux during intravenous infusions of massive doses of histamine, idicating that this edemogenic agent causes an endogenous release of catecholamines which tend to antagonize the direct actions of histamine on the microvascular membrane via stimulation of beta-adrenergic receptors.
Two receptor forms for ouabain in sarcolemma-enriched preparations from canine ventricle.
Authors: Wellsmith N V , Lindenmayer G E
Published: June 2012

Some evidence indicates that the inotropic effect of cardiac glycosides occurs at concentrations too low to affect Na+,K+-ATPase activity. This suggests that some receptor other than Na+,K+-ATPase mediates the inotropic effect. We studied ouabain binding to sarcolemma-enriched preparations from canine ventricle under conditions known to promote binding to Na+,K+-ATPase. Profiles for binding and dissociation were characterized by two kinetic components: (1) fast association and slow dissociation; (2) slow association and fast dissociation. Profiles in the absence of supporting ligands were consistent with a single species of receptors with slow association, fast dissociation and minimal effect on Na+,K+-ATPase activity. Binding supported by magnesium plus inorganic phosphate inhibited Na+,K+-ATPase activity by 86%. The two binding components were affected differentially by heating at 55 degrees C. It was concluded that the preparation possesses two receptors for ouabain: the Na+,K+-ATPase and a "new" receptor. The latter may be different chemically from the Na+,K+-ATPase. The more likely possibility is that the "new" receptor is the Na+,K+-ATPase in a state characterized by low catalytic activity, low affinity for ouabain, and no requirement of specific ligands for ouabain binding. Further, the data suggest an interdependence between the two forms. This leads to a mechanism which allows an inotropic effect to precede loss of Na+,K+-ATPase activity even though both result from glycoside binding to Na+,K+-ATPase. The mechanism involves an equilibrium between inactive and active forms of the Na+,K+-ATPase such that the inactive form buffers loss of the active form upon exposure to a cardiac glycoside.
The effects of acetylstrophanthidin and ouabain on the sympathetic adrenergic neuroeffector junction in canine vascular smooth muscle.
Authors: Lorenz R R , Powis D A , Vanhoutte P M , Shepherd J T
Published: June 2012

We performed experiments to determine the effects of acetylstrophanthidin (ACS) and ouabain on the adrenergic neuroeffector junction in dog saphenous veins. In quiescent strips incubated with 3H-norepinephrine (3H-NE), the drugs caused contraction and a progressive increase in overflow of 3H-NE and O-methylated metabolites; 3,4-dihydroxyphenylglycol (DOPEG) decreased. Tissue uptake of 3H-NE was partially inhibited. After surgical sympathectomy, both contraction and 3H-NE overflow were markedly attenuated. Following chemical sympathectomy with 6-hydroxydopamine, ouabain contractions were 11% of control, whereas the contractions due to exogenous norepinephrine were exaggerated. The initial overflow of 3H-NE was unaffected by tetrodotoxin, but the later and larger overflow with prolonged exposure was depressed. The former occurred in the absence of Ca2+, but the latter was Ca2+ dependent. Inhibition of the neuronal amine carrier by cocaine or desipramine and blockade of the neuronal alpha-adrenoceptors with phentolamine or phenoxybenzamine attenuated the release of 3H-NE evoked by ACS and ouabain. During electrical stimulation, ACS augmented the overflow of 3H-NE. This was attenuated by cocaine, desipramine, and the alpha-adrenolytic drugs. ACS, like pargyline, augmented the overflow of 3H-NE evoked by tyramine and depressed that of DOPEG. These experiments suggest that acetylstrophanthidin and ouabain (1) cause contraction of vascular smooth muscle by displacement of norepinephrine from neuronal stores, (2) reduce neuronal monoamine oxidase activity, (3) facilitate and may trigger Ca2+-dependent exocytotic release of norepinephrine, (4) partially inhibit the neuronal amine carrier mechanism but do not interfere with extraneuronal disposition of norepinephrine, and, finally (5) may have unexplained interactions with prejunctional alpha-adrenoceptors.
Effects of renal and hepatic venous congestion on renal function in the presence of low and normal cardiac output in dogs.
Authors: Priebe H J , Heimann J C , Hedley-Whyte J
Published: June 2012

We investigated the effect of acute renal vein and hepatic vein hypertension induced by partial balloon-occlusion of the abdominal inferior vena cava (AIVC-O) and the thoracic inferior vena cava (TIVC-O) on systemic and renal hemodynamics and renal function in 13 dogs anesthetized with pentobarbital. When a renal vein pressure of 13 cm H2O was induced by AIVC-O, cardiac output, stroke volume, central venous pressure, renal blood flow, and renal function (GFR, free water clearance, osmolar clearance, urine output, urinary sodium excretion, fractional sodium excretion) decreased significantly. When systemic hemodynamics were restored to control values by transfusion of autologous blood (mean of 9 ml/kg body weight) while renal vein pressure was kept elevated, renal function also was restored. A hepatic venous pressure of 13 cm H2O then was induced by TIVC-O. The effects on systemic hemodynamics and renal function were very similar to those observed during AIVC-O. When systemic hemodynamics were restored to control values by transfusion (mean of 9 ml/kg), while hepatic venous hypertension was maintained by TIVC-O, renal function also was restored. Despite significant changes in natriuresis and diuresis, intrarenal blood flow distribution, as determined by the radioactive microsphere technique, remained essentially unchanged throughout. We conclude that renal and hepatic congestion induced by partial AIVC-O and TIVC-O do not, per se, alter renal function significantly.
Carotid sinus baroreceptor reflex control of the circulation in medial sclerotic and renal hypertensive rabbits and its modification by the aortic baroreceptors.
Authors: Angell-James J E , George M J
Published: June 2012

We studied the reflex control of blood pressure, heart rate, and hindlimb vascular resistance by the carotid sinus baroreceptors in normal (N), experimental renal hypertensive (RH, one kidney renal wrap model), and medial sclerotic (MS) rabbits under urethane anaesthesia using an isolated perfused carotid sinus preparation and auto-perfused hindlimb. The contralateral carotid sinus was denervated. Compared to N rabbits, the blood pressure and hindlimb vascular resistance of RH and MS rabbits were significantly elevated at all carotid sinus pressures 15 weeks after inducing the disease process. The maximum gains of the curves relating carotid sinus pressure to vascular resistance were significantly elevated in the MS and RH rabbits, but those relating carotid sinus pressure to heart rate were significantly reduced. The changes were greatest in the RH group in which the responses also were set to a higher carotid sinus pressure. In the three groups, division of the aortic nerves produced different changes in the sigmoid curves relating carotid sinus pressure to heart rate, blood pressure, and vascular resistance. There was a linear relationship between blood pressure and basal vascular resistance (correlation coefficient 0.88).
Reduction of maximal coronary vasodilator capacity in conscious dogs with severe right ventricular hypertrophy.
Authors: Murray P A , Vatner S F
Published: June 2012

Right coronary reactive hyperemia and the maximal coronary vasodilator response to adenosine were examined in conscious, normal dogs and dogs with right ventricular (RV) hypertrophy. RV hypertrophy was induced by chronic (5-7 months) pulmonary artery stenosis. With RV hypertrophy, RV weight to body weight ratio rose by 70% (P < 0.001), right coronary artery blood flow (Doppler ultrasonic technique) rose from 17 +/- 1 to 51 +/- 5 ml/min, and RV transmural blood flow (radioactive microsphere technique) increased from 0.78 +/- 0.06 to 1.62 +/- 0.10 ml/min per g, while the RV endocardial:epicardial perfusion ratio decreased from 1.36 +/- 0.04 to 1.0 +/- 0.02. Excess blood flow debt repayment following release of a 15-second right main coronary artery occlusion was attenuated markedly (P < 0.001) to 107 +/- 22% from the normal value of 325 +/- 41%. Maximal coronary vasodilator capacity (to iv adenosine) was reduced in the hypertrophied right ventricle, as reflected by a lower (P < 0.05) level of maximal transmural blood flow and a higher (P < 0.02) level of minimum coronary vascular resistance per gram of hypertrophied right ventricle compared to normal. During maximal coronary vasodilation, the endocardial:epicardial perfusion ratio decreased (P < 0.001) below unity in the hypertrophied right ventricle to a level (0.83 +/- 0.06) significantly lower (P < 0.001) than normal (1.16 +/- 0.03). Thus, the development of severe RV hypertrophy is characterized by an attenuated coronary response to acute ischemia and by a reduction in maximal coronary vasodilator capacity. We conclude that the increase in cardiac mass which results from chronic pulmonary artery stenosis is not accompanied by a proportionate increase in cross-sectional area of coronary vessels supplying the hypertrophied ventricle.
pH-dependent electrophysiological effects of quinidine and lidocaine on canine cardiac purkinje fibers.
Authors: Nattel S , Elharrar V , Zipes D P , Bailey J C
Published: June 2012

We used standard microelectrode techniques to evaluate the effects of lidocaine and quinidine on canine Purkinje fibers at normal pH (7.3) and in the presence of acidosis (pH 6.9). Acidosis alone reduced resting potential, action potential amplitude, and Vmax, while increasing APD90 and conduction time. Lidocaine concentrations of 6 x 10(-6) to 1.5 x 10(-5) M had minimal effect on resting potential, action potential amplitude, and Vmax at pH 7.3. At pH 6.9, the same lidocaine concentrations significantly reduced resting potential (3-10%), action potential amplitude (3-8%) and Vmax (14-22%). Quinidine (6 x 10(-6) to 1.5 x 10(-5) M) reduced resting potential (3-5%), action potential amplitude (4-9%), and Vmax (19-34%) at pH 7.3. At pH 6.9, quinidine produced significantly greater reductions in resting potential (4-15%), action potential amplitude (5-18%), and Vmax (22-49%). These changes were associated with much more quinidine- and lidocaine-induced prolongation of interelectrode conduction time at acidic than at normal pH. Inexcitability occurred at pH 6.9 in four of 14 experiments with 1.5 x 10(-5) M quinidine and in two of 10 with 1.5 x 10(-5) M lidocaine, and was reversed at the same drug concentration by normalizing pH. Acidosis did not alter the Vmax-resting potential relationship in either the absence or presence of antiarrhythmic agents. Furthermore, changes in ionization did not account for the alterations in electrophysiological effects of quinidine and lidocaine produced by acidosis. Our data suggest that extracellular pH changes may modify importantly the effects of antiarrhythmic agents.
Age dependence of myocardial Na+-K+-ATPase activity and digitalis intoxication in the dog and guinea pig.
Authors: Marsh A J , Lloyd B L , Taylor R R
Published: June 2012

Infants and young animals tolerate higher doses of digitalis glycosides, relative to body weight, than adults. One possible explanation for this could be an age-dependent difference in the myocardial digitalis receptor, the Na+-K+-ATPase. Two functions of this enzyme were studied in adult, 1- and 6-week-old dogs and guinea pigs: in vitro myocardial uptake of rubidium (86Rb) and binding of ouabain. In guinea pigs, rubidium uptake (pmol Rb/mg LV per 15 min) was: 1 week old: 100.9 +/- 7.1 (mean +/- SE); 6 week: 79.8 +/- 6.7 adult: 55.2 +/- 7.9; (1 week: 6 week: P less than 0.025; 1 week: adult, P less than 0.001; 6 week: adult, P less than 0.025). Similarly in dogs, rubidium uptake was significantly greater at 1 week than at 6 weeks (208 +/- 13 vs. 144 +/- 9; P less than 0.001) and the latter greater than in adults (111 +/- 4) (P less than 0.005). Other groups of anesthetized adult and 6-week-old dogs were given digoxin, 0.3 mg/kg, iv. The young dogs took significantly longer to become cardiotoxic (17.3 +/- 3.4 min vs. 9.3 +/- 1.4 min; P less than 0.025), while their myocardial digoxin uptake was at least as great. Rubidium uptake showed an average decrease of 56% after digoxin but residual uptakes were not different in the two groups. Data for ouabain binding showed similar differences between the various groups of dogs studied. Increased myocardial Na+-K+-ATPase activity, reflected in greater active cation transport and specific enzyme binding, has been demonstrated in young animals and may be partly responsible for their greater tolerance to digitalis glycosides.
Diffusional shunting in the canine myocardium.
Authors: Roth A C , Feigl E O
Published: June 2012

A test for the existence of a diffusional shunt in the myocardium was performed in closed-chest, chloralose-anesthetized dogs. Coronary blood flow was varied from 0.21 to 1.17 ml/min per g with a roller pump via a stainless steel coronary perfusion cannula. Following intracoronary artery bolus indicator injection, the coronary sinus venous appearance times of hydrogen, plasma protein labeled with indocyanine green dye, and red blood cells labeled with 99mTc were measured. Venous appearance time was calculated, either as the time from injection until the indicator reached 5% of its peak venous concentration or the time from injection until 0.1% of the injected material arrived at the coronary sinus. At low coronary flow rates (0.4 sec dye appearance time) hydrogen appearance preceded by about 1 second the appearance of the intravascular 99mTc-labeled red blood cells and the dyed plasma, indicating that hydrogen traversed an extravascular shunt path from small arteries to veins. As flow was increased, this hydrogen precession was reduced, and at high flows detectable levels of hydrogen arrived in the coronary sinus after the intravascular indicators. The difference in appearance time between hydrogen and the intravascular indicators was related linearly to the dye appearance time (proportional to l/flow), as would be expected with diffusional shunting. These data indicate that there is arterial-venous shunting of hydrogen in the myocardium. Furthermore, diffusional shunting may be important in the delivery of oxygen to, or removal of carbon dioxide from, the heart.
Chronic progressive pressure overload of the cat right ventricle.
Authors: Cooper G , Tomanek R J , Ehrhardt J C , Marcus M L
Published: June 2012

When an abrupt, fixed increase in afterload induces hypertrophy, the myocardium exhibits normal pump function in vivo, depressed muscle function in vitro, and paradoxically increased oxygen consumption. Such abnormalities may be either a transient response to a reversible myocardial injury or instead may be a persistent characteristic of hypertrophy contributing to eventual heart failure. To distinguish between these alternatives, we developed a model of chronic progressive pressure overload. Kittens had either a sham operation or pulmonary banding for 25 (group I) or 60 (group II) weeks. Banding produced a gradually increasing pressure overload with growth, maximum at 16 weeks after operation. The ratio of right ventricular to body weight increase from 0.54 +/- 0.03 to 0.82 +/0.04 g/kg (P less than 0.01) in group I and from 0.50 +/- 0.03 to 0.72 +/- 0.03 (P less than 0.01) in group II. In vivo right ventricular pump function (cardiac output and ejection fraction) was normal in both groups. In vitro contractile function and metabolism were measured in papillary muscles from the same right ventricles. Both experimental groups showed marked contractile abnormalities: preloaded shortening velocity was reduced from 0.80 +/- 0.05 to 0.53 +/- 0.05 muscle length/sec (P less than 0.01) in group I and from 0.84 +/- 0.04 to 0.60 +/- 0.06 (P less than ).01) in group II. Maximum isometric active tension was reduced from 60 +/- 7 to 35 +/- 5 mN/mm2 (P less than 0.01) in group I and from 56 +/- 5 to 27 +/- 4 (P less than 0.01) in group II. Metabolism was normal in both experimental groups. Thus, under conditions relevant to the study of clinical cardiac hypertrophy that are unlikely to cause acute injury, hypertrophy produces persistently abnormal intrinsic contractile function
Phosphorylation and adenosine triphosphatase activity of myofibrils from thyrotoxic rabbit hearts.
Authors: Litten R Z , Martin B J , Howe E R , Alpert N R , Solaro R J
Published: June 2012

Cardiac hypertrophy induced by thyrotoxic stress leads to an increase in the rate of force development, velocity of shortening, tension-dependent heat generation, and myosin ATPase activity. We did studies to see whether alterations in covalent phosphorylation of myofibrillar proteins correlate with these changes. The protein preparations were isolated from control and thyrotoxic hearts of male albino rabbits freeze-clamped in situ. We measured myofibrillar ATPase, and the covalent phosphate content of ventricular myosin 19,000 (mol wt) light chain (P-light chain) and troponin I (TnI). The myofibrillar ATPase activity was increased 2-fold in the thyrotoxic preparations with no change in the level of myofibrillar phosphorylation. The covalent phosphate content of TnI was 1.21 +/- 0.09 mol P/mol TnI in control hearts and 1.14 +/- 0.04 mol P/mol TnI in thyrotoxic hearts. The covalent phosphate content of the light chain fraction was 0.41 +/- 0.06 mol P/mol P-light chain in control hearts and 0.37 +/- 0.04 mol P/mol P-light chain in thyrotoxic hearts. The dependence of the normalized myofibrillar ATPase on free calcium concentration was the same in control and thyrotoxic preparations. Thus the mechanical, thermal, and biochemical changes found in hearts from thyrotoxic animals probably occur with no change in phosphorylation of TnI or myosin light chains.
Oscillatory afterpotentials in dog ventricular muscle fibers.
Authors: Hiraoka M , Okamoto Y , Sano T
Published: June 2012

Ventricular muscle fibers from dog hearts were superfused with K+-free, high Ca2+ solutions after exposure to a K+-free, Ca2+-free superfusate. Following a series of driven action potentials, oscillatory after potentials (OAPs) were elicited in all 40 preparations at a resting potential of greater than -60 mV. The OAPs appeared not to represent either an electrotonic influence from Purkinje fibers or reentry. They showed a non-monotonic dependence on the basic cycle length, as well as on the number of preceding action potentials. When the OAPs attained threshold, there was extra-excitation (triggered activity) and, occasionally, sustained rhythmic activity. Single premature impulses increased the amplitude of the OAPs, but single or multiple stimuli applied during sustained rhythmic activity failed to stop it. The amplitude of the OAPs increased with higher external [Ca2+] and with lower external [Na+]. The OAPs and triggered activity were suppressed in the presence of Mn2+, verapamil, and 2.7 mM K+. Our results indicate that OAPs and triggered activity can be evoked in the working myocardium at normal resting potentials under various conditions, and that they represent abnormal impulse formation rather than reentry.
The opposing effects of chronic angiotensin-converting enzyme blockade by captopril on the responses to exogenous angiotensin II and vasopressin vs. norepinephrine in rats.
Authors: Spertini F , Brunner H R , Waeber B , Gavras H
Published: June 2012

To study the influence of acute and chronic angiotensin-converting enzyme blockade on the pressor response to exogenous angiotensin II, vasopressin and norepinephrine, we gave normal female Wistar rats 100 mg of captopril or 1 ml of 5% glucose twice daily by gavage for 2 weeks. On the 15th day, rats were anesthetized with pentobarbital, and dose-response curves to angiotensin II, lysine-vasopressin, and norepinephrine were obtained before and after intraperitoneal injection of 100 mg/kg of captopril or 1 ml of 5% glucose. Acute as well as chronic converting enzyme blockade enhanced the pressor response to exogenous angiotensin II. Similarly, sensitivity to exogenous vasopressin was increased by both acute and chronic converting enzyme inhibition. In contrast, chronic converting enzyme blockade significantly blunted the response to exogenous norepinephrine, whereas acute blockade tended to accentuate its pressor effect. These results suggest that chronic angiotensin-converting enzyme blockade may partly inhibit sympathetic activity which, in turn, might contribute to the antihypertensive efficacy of this therapeutic approach. These results also point to an important physiological interaction between the two pressor hormones, angiotensin II and vasopressin.