Effects of acute ischemia in the dog on myocardial blood flow, beta receptors, and adenylate cyclase activity with and without chronic beta blockade.

Abstract

We ligated the left anterior descending coronary artery for 1 or 2 h in 31 purebred beagles. We did not detect any changes in ,8-adrenergic receptor density or affinity when normal and ischemic zones were compared, either in the subendocardium or in the subepicardium. In the ischemic zones, there was a significant decline in all measures of adenylate cyclase activity, including activity mediated by the ,-adrenergic receptor. By contrast, after chronic fl-adrenergic blockade (1.5 mg/kg propranolol i.v. twice daily for 7 d), there was an increase in adenylate cyclase activity stimulated by (-)-isoproterenol relative to adenylate cyclase activity stimulated by guanyl-5'imidodiphosphate (GppNHp) in both normal and ischemic tissue, suggesting that one effect of chronic ,B blockade may be to enchance coupling between the stimulatory guanine nucleotide regulatory protein (Gs) and the fl-adrenergic receptor, despite a reduction in the number or function of Gs units. Chronic ,B blockade also led to up regulation of ,-adrenergic receptor density in subepicardial regions. After 20 min of reperfusion following 2 h of ischemia, adenylate cyclase activity tended to return to control levels, particularly in the subepicardium, where (-)-isoproterenol-stimulated adenylate cyclase activity was not different from normal myocardium. We conclude that chronic f-adrenergic blockade may have beneficial effects during prolonged episodes of myocardial ischemia by preserving signal transduction mediated by the ,-adrenergic receptor.

Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart.

“…For example, a recent study (34) showed that propranolol, a nonselective /3-adrenergic receptor antagonist, resulted in increased net isoproterenol-stimulated cAMP production in ca- (1,34). Potential mechanisms underlying this alteration in adrenergic signaling include alterations in receptor number, in receptor-agonist affinity, or in receptor-Gsa coupling.…”

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

“…In contrast, uncoupling of ,B, receptors may be the result of local ischemia (13,57), whereas decreased adenylate cyclase catalytic activity may be secondary to load-dependent tissue injury (45,46). These changes involving the powerful contractility-regulating receptor-G protein-adenylate cyclase pathway in the human heart indicate that this system has multiple potential regulatory sites, and the diversity of changes in different types of heart muscle disease illustrate the "model dependency" (9, 56) ofthe system.…”

Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia.

“…The collateral-dependent region has normal function at rest, but, because of insufficient vascular reserve, has abnormal function when myocardial oxygen demands are increased. Important changes in myocardial f-adrenergic receptor (fAR)' expression have been found in animal models after complete coronary artery occlusion leading to myocardial infarction (3)(4)(5)(6)(7). In general, FAR upregulation is observed, a sequelae perhaps ofexternalization of cytosolic receptors previously sequestered by energy-dependent processes.…”

“…Some studies have found increased isoproterenol-stimulated adenylyl cyclase activity after acute severe myocardial ischemia (5), but most find decreased activity. Karliner et al (6) recently evaluated 3AR expression and adenylyl cyclase activity after 1-2 h of coronary occlusion in dogs. J3AR-mediated and stimulatory GTP-binding protein (Gs)-mediated cAMP production were 30-50% reduced in the ischemic regions of the left ventricle.…”