Tricuspid Avulsion Research Articles

Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF.

Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, beta-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre- and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [(3)H]NE, beta-receptor density by [(125)I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial beta-adrenoceptor density and beta-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial beta-adrenoceptor density and beta-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.

ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure.

Cardiac sympathetic nerve terminal dysfunction plays an important role in the downregulation of myocardial beta-adrenoceptors in heart failure. To determine whether chronic angiotensin-converting enzyme (ACE) inhibition improved cardiac sympathetic nerve terminal function and hence increased myocardial beta-adrenergic responsiveness, we administered ACE inhibitors to dogs with chronic right-sided heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. The RHF animals exhibited fluid retention, elevated right heart filling pressures, blunted inotropic response to isoproterenol, and reduced beta-adrenoceptor density. These changes were accompanied by decreases in right ventricular norepinephrine (NE) uptake and neuronal NE histofluorescence and tyrosine hydroxylase immunoreactive profiles. ACE inhibitors had no effect on the production of heart failure but greatly reduced the attenuation of cardiac NE uptake, neuronal NE histofluorescence, and tyrosine hydroxylase immunoreactive profiles. ACE inhibition also improved the inotropic response to isoproterenol and restored myocardial beta-adrenoceptor density. The changes probably are caused by reduction of cardiac NE release by ACE inhibition and may contribute to the beneficial effects of ACE inhibitor therapy in patients with chronic heart failure.

Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol.

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.

Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure.

We have shown previously that norepinephrine (NE) uptake activity is reduced in the failing right ventricle of animals with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary constriction. However, it is unknown whether this defect in neuronal NE uptake is related to reduction of noradrenergic nerve terminals or whether these changes also occur in animals with left heart failure (LHF). It is also unknown whether increased NE release in heart failure contributes to the noradrenergic nerve abnormalities. We measured myocardial NE content. NE uptake function, and noradrenergic nerve profiles in dogs with either RHF or LHF induced by rapid ventricular pacing. NE uptake activity was measured using [3H]NE, and noradrenergic nerve profiles were visualized by glyoxylic acid (SPG)-induced histofluorescence and tyrosine hydroxylase immunocytochemical staining. To study the effects of excess NE, we exposed normal dogs to 8 weeks of chronic NE infusion using subcutaneous osmotic minipumps. RHF and LHF animals exhibited reduced myocardial contractile function and congestive heart failure, as evidence by reduced cardiac output and elevated right atrial pressure. However, unlike that in LHF, left atrial pressure was not increased in RHF. The animals also showed an increase in plasma NE and a decrease in cardiac NE. In addition, SPG-induced histofluorescence correlated significantly with NE uptake activity (r = .712, P < .001) and tyrosine hydroxylase immunoreactive profiles (r = .569, P < .001) in the right ventricles of RHF dogs and in both ventricles of LHF dogs. The numbers of catecholaminergic profiles and tyrosine hydroxylase profiles significantly correlated with cardiac filling pressures. Chronic infusion of NE decreased heart rate in normal dogs but had no effect on either mean aortic pressure or left atrial pressure; like heart failure, it resulted in significant decreases in myocardial NE uptake activity and numbers of SPG-induced catecholaminergic histofluorescence and immunoreactive tyrosine hydroxylase profiles. Myocardial NE uptake activity was reduced only in the failing ventricles with elevated filling pressure in RHF and LHF. These changes probably were caused by loss of noradrenergic nerve terminals in the failing ventricles, as evidenced by the reductions of catecholaminergic histofluorescence and tyrosine hydroxylase immunostained profiles. Furthermore, since similar reductions of myocardial NE uptake and noradrenergic nerve profiles could be produced by chronic NE infusion in normal dogs, elevated NE levels may play a role in the development of cardiac noradrenergic nerve abnormalities in congestive heart failure.

Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive heart failure.

The endogenous opiate system is activated in congestive heart failure. because endogenous opioids are known to depress the baroreflex function, we conducted studies to determine whether the increased endogenous opioids play a role in causing the reduced baroreflex function that occurs in heart failure. Right-sided congestive heart failure was produced in 16 dogs by tricuspid avulsion and progressive pulmonary artery constriction. Seven sham-operated dogs were included for comparison. Baroreflex function was measured in the conscious dogs after pretreatment with either normal saline or an opiate-receptor antagonist by bolus administration of phenylephrine. The slope of the regression line relating systolic blood pressure to cardiac cycle (R-R) interval was taken as an index of baroreflex sensitivity. Plasma beta-endorphin was elevated in the dogs with heart failure (15.3 +/- 2.5 pmol/l) compared with the sham-operated dogs (4.2 +/- 0.4 pmol/l, p less than 0.001). The dogs with heart failure also exhibited a reduced baroreflex sensitivity (3.84 +/- 0.19 msec/mm Hg) after saline pretreatment when compared with the sham-operated dogs (10.86 +/- 1.20 msec/mm Hg, p less than 0.001). Administration of naloxone hydrochloride increased the baroreflex sensitivity of dogs with heart failure to 5.16 +/- 0.26 msec/mm Hg (p less than 0.01) but produced no significant effects in sham-operated dogs (11.36 +/- 1.42 msec/mm Hg). To further study the site of action for the effect of naloxone, we measured baroreflex sensitivity in the dogs with heart failure after pretreatment with naloxonazine, a selective mu-receptor antagonist, with ICI 154,129, a selective delta-receptor antagonist, or with naloxone methobromide, a quaternary analogue of naloxone that does not penetrate the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonist-induced homologous desensitization. However, recent evidence suggests that excessive adrenergic stimulation may not produce myocardial beta-receptor downregulation unless there is an additional defect in the local norepinephrine (NE) uptake mechanism. To investigate the association between beta-adrenoceptor regulation and NE uptake activity, we carried out studies in 30 dogs with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary artery constriction and 23 sham-operated control dogs. We determined NE uptake activity by measuring accumulation of [3H]NE in tissue slices, NE uptake-1 carrier density by [3H]mazindol binding and beta-adrenoceptor density by [3H]dihydroalprenolol binding. Compared with sham-operated dogs, RHF dogs showed a 26% decrease in beta-adrenoceptor density, a 51% reduction in NE uptake activity, and a 57% decrease in NE uptake-1 carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-1 carrier density. In contrast, neither NE uptake activity nor beta-receptor density in the left ventricle and renal cortex was affected by RHF. Thus, the failing myocardium is associated with an organ- and chamber-specific subnormal neuronal NE uptake. This chamber-specific loss of NE uptake-1 carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

Tricuspid valve avulsion or excision for right ventricular decompression in pulmonary atresia with intact ventricular septum

Retrograde right ventricular decompression through the tricuspid valve, by damaging or excising the valve, was attempted in five patients with pulmonary atresia, intact ventricular septum, and severely hypoplastic right ventricle. Two patients were neonates in critical condition, one of whom had received previous palliation with a shunt; the other neonate had received pulmonary valvotomy plus shunt followed by repeat valvotomy plus shunt ligation. Three patients were infants or children who had undergone placement of isolated neonatal shunts. One procedure was performed during cardiac catheterization. Three patients survived. In one, tricuspid avulsion and a Rashkind septostomy were done by percutaneous methods; in two patients, tricuspid excision plus bidirectional cavopulmonary anastomosis was done by open operation. At restudy, all showed subsystemic pressure in the right ventricle and diminution or disappearance of sinusoids. One also showed improvement of left ventricular function. Incorporation of a small right ventricle in the right atrium at the time of the two orthoterminal palliations seemed, at least, innocuous. Right ventricular decompression by tricuspid avulsion or excision could be suggested for all patients with pulmonary atresia, intact ventricular septum, hypersystemic hypoplastic right ventricle, and major sinusoids without right ventricular dependent coronary circulation in whom the outlet portion of the right ventricle is not functional.

Short-term hemodynamic effects of vasopressin V1-receptor inhibition in chronic right-sided congestive heart failure.

Arginine vasopressin is elevated in congestive heart failure. To determine the effect of arginine vasopressin upon systemic hemodynamics and regional blood flows, we administered the specific inhibitor of the vascular action of vasopressin [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-methyl)-tyrosine]-arginine vasopressin [d(CH2)5Tyr(Me)AVP] to 15 dogs with chronic right-heart failure produced by tricuspid avulsion and progressive pulmonary artery constriction. The animals exhibited increased plasma arginine vasopressin and norepinephrine levels. Vasopressin inhibition increased cardiac output and left ventricular dP/dt and dP/dt/P, and it decreased total peripheral vascular resistance, whereas mean aortic pressure did not change significantly. Simultaneously, blood flow increased to skeletal muscle, kidneys, skin, and right and left ventricular myocardium. Plasma catecholamines also increased. Pretreatment with propranolol and prazosin abolished the increases in cardiac output and left ventricular function produced by vasopressin inhibition. Pretreatment also led to a decrease in mean aortic pressure after vasopressor inhibition. In contrast, administration of d(CH)2)5Tyr(Me)AVP to 11 sham-operated animals or administration of normal saline to nine sham-operated and eight heart-failure dogs was without effect either in the absence or in the presence of adrenergic receptor blockade. Thus, arginine vasopressin participates in the control of the circulation in right-sided congestive heart failure, with both a direct constrictor action on blood vessels and an indirect action by inhibition of the sympathetic nervous system.

Effects of Milrinone on Systemic Hemodynamics and Regional Circulations in Dogs with Congestive Heart Failure

Milrinone is a new bipyridine inotropic agent with direct vasodilator properties. To determine the role of the vasodilator action in mediating systemic and regional hemodynamic responses to milrinone, we administered two equipotent inotropic doses of either milrinone or dobutamine to dogs with chronic congestive right heart failure produced by tricuspid avulsion and pulmonary artery stenosis. Similar increases in cardiac output, right and left ventricular dP/dt, and left ventricular dP/dt/P were produced by milrinone and dobutamine; however, heart rate increased and mean aortic pressure decreased only with milrinone infusion. In addition, while total peripheral vascular resistance decreased with both agents, the decrease was greater with milrinone. Regional blood flows were measured by a radioactive microsphere method. Milrinone and dobutamine produced similar increases in myocardial blood flow and left ventricular oxygen consumption. Dobutamine infusion decreased quadriceps muscle vascular resistance and had no effect on renal and splanchnic circulations. In contrast, milrinone infusion increased vascular resistance in quadriceps muscle and decreased it in renal and splanchnic beds. Thus, when milrinone was used in inotropic doses similar to those of dobutamine, the responses in systemic and regional hemodynamics in congestive heart failure differed. Milrinone produced a greater decline in total peripheral, renal, and splanchnic vascular resistances, probably resulting from its direct vasodilator action.

Alterations in cardiac β-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs

The effects of congestive heart failure on the physiological and biochemical functions of the cardiac β-adrenoceptor-coupled adenylate cyclase system were studied in dogs with right heart failure produced by progressive pulmonary artery constriction and tricuspid avulsion. The cardiac inotropic response to dobutamine was attenuated in congestive heart failure, as determined by the right and left ventricular dP/dt responses. Adrenergic β-receptor density, measured by [ 3H]dihydroalprenolol binding, was reduced in membrane fractions of the failing right ventricle, but not in the left ventricle. The functional activity of the adenylate cyclase system was studied in vitro by measuring the net cyclic AMP production following additions of isoproterenol, 5'-guanylylimidodiphosphate (Gpp(NH)p), forskolin, or manganese chloride, which act either directly on the β-adrenergic receptors or on one of the post-receptor components of the adenylate cyclase system. Congestive heart failure reduced the net production of cyclic AMP by isoproterenol, Gpp(NH)p, and forskolin in both the right and left ventricles, but did not alter the effect of manganese chloride. Thus, β-receptor down-regulation is chamber-specific, occuring only in the hemodynamically stressed right ventricle. In contrast, the post-receptor defect of the adenylate cyclase system occured in both ventricles of the heart failure dogs. This decreased activation of adenylate cyclase by β-agonists may be responsible, at least in part, for the diminished cardiac inotropic response to catecholamines in congestive heart failure.

The role of endogenous opioids in congestive heart failure: effects of nalmefene on systemic and regional hemodynamics in dogs.

We studied the role of endogenous opiates and their interrelationships with the sympathetic nervous system in an experimental preparation of right-sided congestive heart failure (CHF) produced by surgical tricuspid avulsion and progressive pulmonary arterial constriction. Three groups of dogs with CHF and one group of sham-operated dogs were studied. One group of dogs with CHF was given normal saline as pretreatment, while the other two groups were pretreated with either propranolol alone (beta-blockade) or propranolol plus prazosin (alpha- plus beta-blockade). CHF was characterized by weight gain, ascites, elevated right atrial pressure, tachycardia, and reduced cardiac output. Compared with sham-operated animals, animals with CHF exhibited significantly higher baseline levels of plasma beta-endorphin and cortisol. Furthermore, only the animals with CHF responded to the opiate receptor-antagonist nalmefene with significant increases in plasma beta-endorphin, cortisol, and adrenocorticotropic hormone. Administration of nalmefene increased aortic blood pressure, cardiac output, left ventricular dP/dt and dP/dt/P, and blood flow to the myocardium, skeletal muscle, and kidneys in dogs with CHF, but had no appreciable effects in sham-operated dogs. beta-Receptor blockade abolished the increase in cardiac output, left ventricular performance, and blood flow produced by nalmefene, but had no effect on the pressor response to nalmefene. The increase in mean aortic pressure in the beta-blockade group was accompanied by an increase in skeletal muscle vascular resistance. Addition of prazosin in the alpha- plus beta-blockade group abolished the increases in mean aortic pressure and skeletal muscle vascular resistance, suggesting that the changes after propranolol probably resulted from unmasking of alpha-receptor-mediated vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical indices of autonomic innervation of heart in different experimental models of heart failure.

Parasympathetic neural regulation of the failing heart is impaired. In order to investigate parasympathetic mechanisms in experimental heart failure, measurements were made of choline acetyltransferase (CAT) activity and [3H]-quinuclidinyl benzilate (QNB) binding in hearts of 1) hamsters with skeletal and cardiac myopathy, 2) dogs with pulmonary artery constriction and tricuspid avulsion, and 3) guinea pigs with pulmonary artery constriction. Tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) activities and norepinephrine levels served as indices of sympathetic innervation. In myopathic hearts, total CAT activity decreased (P less than 0.05) compared to age-matched controls. In canine and guinea pig right heart failure, total CAT activity was normal in contractile and specialized tissues. Alterations in [3H]-QNB binding paralleled CAT activity being decreased (P less than 0.05) only in myopathic hearts. In all three models, indices of sympathetic innervation were altered in ways qualitatively different from parasympathetic indices; TH and DBH activities were increased (P less than 0.05) in myopathic ventricles, decreased (P less than 0.05) in hypertrophied canine and guinea pig ventricles and non-hypertrophied canine ventricles, and normal in non-hypertrophied guinea pig ventricles. These results indicate that alterations in cardiac parasympathetic indices vary depending on the etiology of heart diseases and differ qualitatively from alterations in sympathetic indices. Selective determinants are necessary to explain the varied changes.

Biochemical indices of cholinergic and adrenergic autonomic innervation in dog heart: Disparate alterations in chronic right heart failure

Abnormal reflex sympathetic and parasympathetic control of heart rate occurs in canine right heart failure. Therefore, we investigated the activities of enzymes catalyzing synthesis of acetylcholine (choline acetyltransferase) and norepinephrine (tyrosine hydroxylase and dopamine-β-hydroxylase) to assess possible mechanisms of altered parasympathetic and sympathetic function respectively in hearts of dogs with chronic (greater than 2 years) right heart failure produced by tricuspid avulsion and pulmonary artery constriction ( n = 7) and sham animals ( n = 7). In dogs with tricuspid avulsion and pulmonary artery constriction there was a reduction in sympathetic neuroenzymes in both the stressed right ventricle and non-stressed left ventricle without any alteration in the parasympathetic neuroenzymes in these regions. There were no detectable changes in any enzyme activities within the left atrium. In the right atrium, however, significant reductions occurred in both sympathetic and parasympathetic neurochemical indices in the region of the sinoatrial node. The variable pattern of cardiac sympathetic and parasympathetic changes in dogs with tricuspid avulsion and pulmonary artery constriction suggests the possbility of non-uniform alterations in autonomic neural control of the chronically diseased heart.

Postprandial redistribution of regional blood flow at rest and during exercise in conscious dogs with experimental heart failure

The effects of eating and of exercise on regional hemodynamics were studied in conscious dogs with chronic right heart failure induced by tricuspid avulsion and progressive pulmonary constriction. Eating a meal induced transient increases in heart rate, arterial pressure and resistance levels in the mesenteric, renal and iliac beds. This response was followed by a prolonged period of increased mesenteric blood flow (+10 percent) and decreased mesenteric vascular resistance (−44 percent), at a time when heart rate and arterial pressure had returned to control levels. Postprandial mesenteric vasodilation was associated with a reduction in iliac blood flow (−20 percent) and an increase in iliac resistance ( + 19 percent) but with little change in renal blood flow and resistance. Strenuous exercise during the period of postprandial mesenteric vasodilation resulted in a 53 percent fall in mesenteric flow from the preprandial control level and a substantial increase in mesenteric vascular resistance. Thus, in dogs with heart failure the ability of the mesenteric bed to respond postprandially with substantial vasodilation persists. However, when the stress of exercise is superimposed, the mesenteric vasodilation is abolished as blood flow to the gut is drastically reduced.

Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis.

In a study of the effects of heart failure on the responses of cardiac receptors, ten dogs were subjected to tricuspid avulsion and pulmonary artery stenosis. One case of spontaneous heart failure was included in the series, and the electrical spike responses of atrial receptors to progressive changes in atrial stretch induced by infusion and hemorrhage were contrasted with those in normal control dogs. In the control dogs, the number of spikes per cycle increased very sharply with moderate, i.e., 5-10 cm H 2 O, venous pressure increments before reaching a maximum at 20 cm H 2 O. In the experimental dogs, the firing rate failed to increase to the same extent despite large increases in pressure. The resulting sets of curves exhibited a sharp dichotomy. This evidence for the impaired response of elements of the subendocardial receptor network is compatible with a decrease in the sensitivity of feedback mechanisms responsible for the regulation of sodium and water metabolism.

Effects of experimentally produced heart failure on the peripheral vascular response to severe exercise in conscious dogs.

The peripheral vascular response to severe exercise in eight dogs with heart failure produced by tricuspid avulsion and progressive pulmonary stenosis was compared to the response determined in eight control dogs. After full recovery from implantation of Doppler flow probes and miniature pressure gauges, measurements of arterial blood pressure and blood flow were telemetered from untethered dogs running behind a mobile recording vehicle at speeds of 10-25 mph over distances averaging 1 mile. Severe exercise in control dogs increased heart rate from 78 to 281 beats/min and mean arterial blood pressure from 93 to 134 mm Hg. Iliac blood flow rose from 151 to 897 ml/min, but mesenteric and renal blood flows did not change significantly. Iliac vascular resistance decreased from 0.64 to 0.15 mm Hg/ml min -1 , but mesenteric vascular resistance increased from 0.31 to 0.47 mm Hg/ml min -1 and renal vascular resistance increased from 0.49 to 0.75 mm Hg/ml min -1 . Severe exercise in dogs with heart failure increased heart rate from 102 to 274 beats/min, but mean arterial blood pressure only increased from 100 to 107 mm Hg. Iliac blood flow rose from 96 to 360 ml/min, whereas mesenteric blood flow decreased from 237 to 89 ml/min and renal blood flow decreased from 226 to 79 ml/min. Iliac vascular resistance decreased from 1.09 to 0.34 mm Hg/ml min -1 , but mesenteric vascular resistance increased from 0.49 to 1.31 mm Hg/ml min -1 and renal vascular resistance increased from 0.47 to 1.81 mm Hg/ml min -1 . Thus, in heart failure a distinctly abnormal peripheral vascular response to severe exercise occurs, characterized by a very small elevation in mean arterial blood pressure and intense visceral vasoconstriction resulting in diversion of visceral blood flows.

Regional hemodynamic effects of a digitalis glycoside in the conscious dog with and without experimental heart failure.

The effects of intravenous ouabain (G-strophanthin), 20 µg/kg, on the superior mesenteric, renal, and external iliac beds were studied over a 30-minute period in eight normal conscious dogs before, and in five of them after, cholinergic blockade and in six conscious dogs with heart failure produced by tricuspid avulsion and progressive pulmonary stenosis. Blood flows were measured with Doppler ultrasonic and electromagnetic flowmeters. In normal dogs, prior to cholinergic blockade, ouabain caused early increases in mesenteric, renal, and external iliac resistances but later, between 15 and 30 minutes, mesenteric resistance decreased below the control level while renal and external iliac resistances remained elevated. After cholinergic blockade, the ouabain-induced alterations in renal and iliac resistance were unaltered, but the later decline in resistance in the mesenteric bed was reversed, resulting in sustained constriction. The late decline in mesenteric resistance also was not observed in the conscious animal after the injection of ouabain, 5 µg/kg, directly into the mesenteric artery or in the majority of dogs given ouabain intravenously after having been anesthetized with pentobarbital sodium. In the conscious dogs with heart failure, ouabain resulted in increased renal and iliac resistances initially, and in vasodilatation later while mesenteric resistance fell initially and remained below control for the entire 30 minutes. Thus, in the normal conscious dog, ouabain causes vasoconstriction in the regional vascular beds, apparently by its direct vascular action, and, in addition, a cholinergically mediated vasodilatation in the mesenteric bed. In the conscious dog with heart failure, ouabain increases blood flow to all beds, reducing the compensatory vasoconstriction of the low output state.

Alterations in the baroreceptor reflex in conscious dogs with heart failure.

The effectiveness of the baroreceptor reflex in conscious dogs with experimental cardiac hypertrophy and heart failure was compared with that in a group of normal conscious dogs. Cardiac hypertrophy and heart failure were produced by tricuspid avulsion and progressive pulmonary stenosis. The sensitivity of the baroreceptor reflex to transient hypertension was assessed by determining the slope of the regression line relating the prolongation of the R-R interval to the rise in systolic arterial pressure during the transient elevation of arterial pressure induced by an intravenous injection of 1-phenylephrine. The mean slope averaged 22.4+/-2.3 msec/nm Hg in 16 normal animals. 23.1 +/-1.5 in five sham-operated animals, and was significantly reduced to 8.3 +/-0.8 in 10 dogs with hypertrophy alone (P < 0.001), and to 3.3+/-0.5 in nine dogs with heart failure (P < 0.001). The response to baroreceptor hypotension was compared during bilateral carotid artery occlusion (BCO) in six normal and six heart failure dogs previously instrumented with Doppler flow transducers on the superior mesenteric and renal arteries. During BCO, in normal dogs arterial pressure increased 52+/-4 mm Hg, heart rate 33+/-2 beats/min, mesenteric resistance 0.17+/-0.03 mm Hg/ml per min, and renal resistance 0.37+/-0.10 mm Hg/ml per min. In the heart failure group all of these variables increased significantly less (P < 0.01); arterial pressure rose 25 +/-3 mm Hg, heart rate 13 +/-4 beats/min, mesenteric resistance 0.04+/-0.007 mm Hg/ml per min, and renal resistance 0.18+/-0.09 mm Hg/ml per min.Thus, in heart failure, all measured systemic and regional circulatory adjustments consequent to baroreceptor hypo- and hypertension are markedly attenuated. This study demonstrates a profound derangement of a major cardiovascular control mechanism in experimental heart failure.