Isoproterenol-Induced Cardiac Hypertrophy: Modifications in Characteristics of β-Adrenergic Receptor, Adenylate Cyclase, and Ventricular Contraction*

The goal of this study was to determine the mechanism of ,/-adrenergic receptor desensitization after chronic elevation of circulating NE levels. Osmotic minipumps containing either NE or saline were implanted subcutaneously in dogs for 34 wk. Physiologic desensitization to isoproterenol was confirmed in conscious dogs, i.e., left ventricular dP/dt increased in response to isoproterenol (0.4 ug/kg per min) by 5,625±731 mmHg/s in control dogs with saline pumps, and significantly less, P < 0.01, by 2,093±263 mmHg/s in dogs with NE pumps. Myocardial 13-adrenergic receptor density as determined with 1251-cyanopindolol binding was 49% higher (P < 0.05) in the NE pump group. However, 13-adrenergic receptor agonist binding with isoproterenol demonstrated a significant shift into the low affinity state for the animals with NE pumps. Basal, GTP plus isoproterenol, 5'-guanylylimidodiphosphate, sodium fluoride, and forskolin-stimulated adenylate cyclase activity in the NE pump group were significantly depressed (P < 0.05) by amounts ranging from 20 to 40%. The functional activity of the guanine nucleotide binding protein G. was also reduced (P < 0.05) in animals with NE pumps. Thus, the process of desensitization in response to chronic elevation of NE levels in intact, normal dogs does not involve a decrease in fi-adrenergic receptor density. Rather, it is characterized by reduced adenylate cyclase activation and uncoupling of the 63-adrenergic receptor in association with decreased activity of the GTP-coupling protein G,.

Section: Discussionmentioning

confidence: 88%

Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Vatner

Nejima

et al. 1989

“…There is, however, evidence to suggest that the increase in sympathetic tone persists (3)(4)(5). Thus, when hypoxemia is prolonged, the benefits of increased sympathetic stimulation may be outweighed by its deleterious cellular, metabolic, and circulatory effects (2,(6)(7)(8). One potential cellular-level consequence of chronic sympathetic stimulation is a down-regulation of the ,B-adrenergic receptor/adenylate cyclase system, as occurs in patients with heart failure secondary to cardiomyopathy (9,10).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of right and left ventricular beta-adrenergic receptors in newborn lambs with experimental cyanotic heart disease.

Bernstein¹,

Voss²,

Huang³

et al. 1990

To determine whether chronic hypoxemia secondary to an intracardiac right-to-left shunt alters regulation of the myocardial 63-adrenergic receptor/adenylate cyclase system, we produced chronic hypoxemia in nine newborn lambs by creating right ventricular outflow obstruction and an atrial septal defect. Oxygen saturation was reduced to 65-74% for 2 wk. Eight lambs served as normoxemic controls. 13-receptor density (B.) and ligand affinity (KD) were determined with the radioligand '2"5iiodocyanopindolol and adenylate cyclase activity determined during stimulation with isoproterenol, sodium fluoride (NaF), and forskolin. During chronic hypoxemia, B.. decreased 45% (hypoxemic, 180.6±31.5 vs. control, 330.5±60.1 fmol/mg) in the left ventricle (exposed to hypoxemia alone) but was unchanged in the right ventricle (exposed to hypoxemia and pressure overload). KD was not different from control in either ventricle. Left ventricular isoproterenolstimulated adenylate cyclase activity was decreased by 39% (30.0±4.3% increase vs. 44.1±9.5% increase) whereas right ventricular adenylate cyclase activity was unchanged. Stimulation of adenylate cyclase with NaF or forskolin was not different from control in either ventricle. Circulating epinephrine was increased fourfold whereas circulating and myocardial norepinephrine were unchanged. These data demonstrate a downregulation of the left ventricular ,6-adrenergic receptor/adenylate cyclase system during chronic hypoxernia secondary to an intracardiac right-to-left shunt. (J. Clin. Invest. 1990. 85:68-74.) cyanotic heart disease -hypoxemia* myocardial fl-adrenergic receptor regulation

“…Prior studies examining the effects of desensitization to catecholamines have been conducted, primarily in vitro (14, 18,19,23) or in acutely prepared anesthetized preparations (15-17, 20, 21) where neural control mechanisms are blunted, ifnot absent. The underlying hypothesis of the present investigation was that neural mechanisms modify importantly the manner in which catecholamine desensitization is expressed primarily to the neurotransmitter NE.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon may be a manifestation of catecholamine desensitization, which has been recognized for some time (11)(12)(13). Most prior studies examining mechanisms of desensitization were conducted in vitro, or in anesthetized animals (14)(15)(16)(17)(18)(19)(20)(21)(22)(23), and have relied primarily on the synthetic 13-adrenergic agonist isoproterenol (ISO),' rather than on the physiological neurotransmitter, NE. The underlying hypothesis of the current investigation was that the mechanism of desensitization to chronic NE would depend upon reflex buffering as well as biochemical mechanisms involving /3-adrenergic receptor pathways in the intact conscious animal, since NE increases arterial pressure and induces baroreflex buffering, resulting in diminished sympathetic neural tone and enhanced parasympathetic restraint.…”

Section: Introductionmentioning

confidence: 99%

Role of intact cardiac nerves and reflex mechanisms in desensitization to catecholamines in conscious dogs.

Nejima¹,

Uemura²,

Vatner³

et al. 1990

To study chronic catecholamine desensitization, mini-osmotic pumps were implanted subcutaneously to deliver NE, (0.5 pg/kg/min) or saline over 3-4 wk in dogs instrumented with left ventricular (LV) pressure gauges and arterial and left atrial pressure catheters. An acute challenge to NE (0.4 pg/kg/min) in intact, conscious dogs increased LV dP/dt by 1,531±208 mmHg/s before NE pumps, and by a similar amount, 1,340±166 mmHg/s, 3-4 wk after NE pumps. In contrast, an acute challenge to isoproterenol (ISO, 0.4 ,ug/kg/min) increased LV dP/dt by 5,344±532 mmHg/s before NE pumps, and significantly less (P < 0.05; 2,425±175 mmHg/s) after NE pumps. In the presence of ganglionic and a,-adrenergic blockades, NE (0.4 pg/kg/min) increased LV dP/dt by 3,656±468 mmHg/s before NE pumps and significantly less (P < 0.01; 1,459±200 mmHg/s) after NE pumps. Confirming this, an acute challenge to NE (0.4 gg/kg/min) in dogs with arterial baroreceptor denervation increased LV dP/dt by 3,732±896 mmHg/s before NE pumps, and significantly less (P < 0.05, 1,725±408 mmHg/s) after NE pumps. In addition, in cardiac denervated dogs, NE (0.4 ;.g/kg/min) increased LV dP/dt by 9,901±1,404 mmHg/s before NE pumps and significantly less (P < 0.01, 2,690±306 mmHg/s) after NE pumps. Desensitization of heart rate responses to NE challenge was also more apparent in the absence of reflex mechanisms. Thus, neural reflex mechanisms play a major role in physiological expression of cardiac desensitization to catecholamines in conscious dogs. (J. Clin.