Mechanism of Norepinephrine Depletion in Experimental Heart Failure Produced by Aortic Constriction in the Guinea Pig

Spann, James F.; Chidsey, Charles A.; Pool, Peter E.; Braunwald, Eugene

doi:10.1161/01.res.17.4.312

Cited by 144 publications

(42 citation statements)

References 19 publications

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“…20 Also, the group with left heart failure produced by constriction of the ascending aorta, LHF A , was analogous to the experimental guinea pig models reported by Gertler, 21 Schwartz and Lee, 22 and Spann and co-workers. 23 The weights of the left ventricles plus septum and the weights of right ventricles were almost identical to those reported for a guinea pig model of left heart failure by Spann et al 23 In agreement with Spann and co-workers, 23 our preparations with left heart failure also exhibited modest right ventricular enlargement. There was no evidence of mottling on the liver surfaces or ascites in our groups with left heart failure, therefore, they did not appear to have signs or symptoms of right heart failure.…”

Section: Vascular Resistance In Heart Failure/sc/i/md Et Alsupporting

confidence: 88%

Differences in the regulation of vascular resistance in guinea pigs with right and left heart failure.

Schmid¹,

Mayer²,

Mark³

et al. 1977

Circulation Research

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SUMMARY We investigated neurogenic, non-neurogenic, and structural contributions to vascular resistance in hindquarters in five groups of guinea pigs after heart failure produced by (1) constriction of the pulmonary artery (RHF), (2) constriction of the ascending aorta (LHF A ), and (3) constriction of the descending thoracic aorta (LHF D ); (4) after left ventricular hypertrophy produced by mild constriction of the ascending aorta (LVH); and (5) after sham surgery. Pressure-flow curves were used to assess vascular resistance in the isolated, perfused hindquarters. In RHF and LHF A , vascular resistance tended to increase and for different reasons. In the LHF A group, sympathectomy produced the greatest vasodilation. Therefore, neurogenic influences predominated. The high neurogenic tone may have been related to reduced arterial pulse pressure (P < 0.05) and reflexes arising in arterial baroreceptors. In contrast, the LHF D group had increased arterial pressure and pulse pressure (P < 0.05) and normal neurogenic vasoconstriction. However, non-neurogenic vasoconstriction was increased probably as a result of increased vascular responsiveness to constrictor stimuli. In the RHF group, papaverine produced the greatest vasodilation (P < 0.05). Therefore, non-neurogenic influences predominated. This was attributed to both increased vascular responsiveness and to altered humoral stimuli. Similar maximal vasodilation indicated that structural factors contributed equally to vascular resistance in all the groups. These results indicate differences in the regulation of vascular resistance in anesthetized, guinea pig models of right and left heart failure.THE RELATIVE importance of neurogenic, humoral, vascular reactive, and structural contributions to vascular resistance in heart failure has not been established. Some investigators have suggested that the neurogenic contribution is predominant. "4 Others have reported observations that detract from this concept. In one study, for example, the reflex vasoconstrictor response to carotid occlusion was less in dogs with right heart failure than in normal dogs. 5 In two other studies reported from our own laboratory, the neurogenic influence, as estimated from the vasodilator response to sympathectomy, was not abnormally increased in hamsters with cardiomyopathy 6 or in dogs with right heart failure. 7 These observations have led us to consider the possibility that various types of heart failure might differ with regard to the relative importance of the factors regulating vascular resistance. Theoretical considerations would appear to support this possibility. Mechanoreceptors in the right and left atria may mediate different compensatory changes. Brennan et al. 8 have suggested that mechanoreceptors in the right atrium modulate plasma levels of renin. Brennan et al. 8 and Johnson et al. reflex control of vascular resistances. Thus, in left and right heart failure, which could stress different populations of mechanoreceptors, the factors contributing to vascular resistance mi...

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Section: Vascular Resistance In Heart Failure/sc/i/md Et Alsupporting

confidence: 88%

Differences in the regulation of vascular resistance in guinea pigs with right and left heart failure.

Schmid¹,

Mayer²,

Mark³

et al. 1977

Circulation Research

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“…Our present study indicates no difference in either spontaneous or tyramine-induced release of NE between the normal and failing right ventricles. Similarly, using an in vivo labeling technique, Spann et al (36) found the absolute levels of specific activity and the rates of disappearance were identical in the left ventricles of normal guinea pigs and those with heart failure produced by aortic constriction. The relative net turnover rates of NE were the same in the normal and failing hearts.…”

Section: Resultsmentioning

confidence: 87%

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

Liang¹,

Fan

Sullebarger³

et al. 1989

J. Clin. Invest.

123

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The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonistinduced 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 betaadrenoceptor 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 IHINE in tissue slices, NE uptake-i carrier density by V3Hlmazindol binding and beta-adrenoceptor density by VHJdihydroalprenolol 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-i carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-i 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-i carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

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“…This phenomenon of reduced tissue norepinephrine levels has been a consistent feature of cardiac failure (32).…”

Section: I3-adrenergicmentioning

confidence: 77%

Effects of pressure overload, left ventricular hypertrophy on beta-adrenergic receptors, and responsiveness to catecholamines.

Vatner¹,

Homcy²,

Sit³

et al. 1984

J. Clin. Invest.

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As bstract. Pressure overload left ventricular (LV) hypertrophy was produced by banding the ascending aorta ofpuppies and allowing them to grow to adulthood. LV free wall weight per body weight increased by 87% from a normal value of 3.23±0.19 g/kg. Hemodynamic studies of conscious dogs with LV hypertrophy and of normal, conscious dogs without LV hypertrophy showed similar base-line values for mean arterial pressure, heart rate, and LV end-diastolic pressure and diameter. LV systolic pressure was significantly greater, P < 0.01, and LV stroke shortening was significantly less, P < 0.01, in the LV hypertrophy group. In both normal and LV hypertrophy groups, increasing bolus doses of norepinephrine or isoproterenol produced equivalent changes in LV dP/dt. disassociation constant (KD) increased, selectively in the LV of the hypertrophy group; the KD in the normal LV was 6.8±0.7 nM compared with 10.7±1.8 nM in the hypertrophied LV. These effects were observed only in the LV of the LV hypertrophy group and not in the right ventricles from the same dogs. The plasma membrane marker, 5' -nucleotidase activity, was slightly lower per milligram protein in the LV hypertrophy group, indicating that the differences in 3-adrenergic receptor binding and affinity were not due to an increase in plasma membrane protein in the LV hypertrophy group. The EC50 for isoproterenol-stimulated adenylate cyclase activity was similar in both the right and left ventricles and in the two groups. However, maximal-stimulated adenylate cyclase was lower in the hypertrophied left ventricle. Plasma catecholamines were similar in the normal and hypertrophied groups, but myocardial norepinephrine was depressed in the dogs with LV hypertrophy (163±48 pg/mg) compared with normal dogs (835±166 pg/mg).Thus, severe, but compensated LV hypertrophy, induced by aortic banding in puppies, is characterized by essentially normal hemodynamics in adult dogs studied at rest and in response to catecholamines in the conscious state. At the cellular level, reduced affinity and increased 3-adrenergic receptor number characterized the LV hypertrophy group, while the EC50 for isoproterenol-stimulated adenylate cyclase activity was normal. By these mechanisms, adequate responsiveness to catecholamines is retained in conscious dogs with severe LV hypertrophy.

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Mechanism of Norepinephrine Depletion in Experimental Heart Failure Produced by Aortic Constriction in the Guinea Pig

Cited by 144 publications

References 19 publications

Differences in the regulation of vascular resistance in guinea pigs with right and left heart failure.

Differences in the regulation of vascular resistance in guinea pigs with right and left heart failure.

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

Effects of pressure overload, left ventricular hypertrophy on beta-adrenergic receptors, and responsiveness to catecholamines.

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