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

Abstract

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.

Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.

“…The adenylate cyclase catalytic subunit defect that appeared to be present in direct relation to the degree of pressure overload in failing human right ventricles is similar to the abnormality in adenylate cyclase that has been previously described in pressure overloaded failing left ventricles in guinea pigs (45) and dogs (46). The agonist affinity status of13-adrenergic receptors in failing human ventricular myocardium has not been previously reported, and the finding of no change in failing myocardium is in disagreement with work in at least one heart failure animal model (47). In this banded aorta, pressureoverload model 13-receptor agonist affinity decreases (47) in conjunction with a decrease in the amount/activities of G, (48) and the adenylate cyclase catalytic subunit (46).…”

Chronic nonocclusive coronary artery constriction in rats. Beta-adrenoceptor signal transduction and ventricular failure.

“…Furthermore, a persistent decrease in ,3-adrenoreceptor antagonist affinity has been reported in a canine model ofpressure overload left ventricular hypertrophy and failure (34,35). At the molecular level, alterations in the transcription of the gene for fl-adrenoreceptors may result in the expression ofa modified primary structure of the receptor protein (35), with a corresponding increase or decrease in receptor antagonist affinity, dependent on the nature of the substitution or deletion.…”

“…Should this be the case, however, the left ventricle would be exposed to a combination of pressure and volume overload stress (5), whereas the right ventricle would be subjected to pressure overload stress only. (33,34) and at the onset of myocardial dysfunction (35) typically shows increases in 13-adrenoreceptor density.…”

Regulation of Sympathetic Activity in Children with Various Congenital Heart Diseases

“…In heart failure, the down-regulation of P-adrenoceptors has been associated with elevated plasma catecholamines, especially norepinephrine (27)(28)(29)(30)(31), whereas changes in a-adrenoceptors appear to be more closely associated with elevations in epinephrine concentrations (32)(33)(34). Although, based on the t test, the elevation in plasma norepinephrine and epinephrine levels was significant only for the PST group, and dopamine in all except the LRS; the percentage increases were similarly remarkable for the other groups.…”