Myocardial beta-AR Research Articles

Right ventricular infundibular beta-adrenoceptor complex in tetralogy of Fallot patients.

Patients with tetralogy of Fallot may have episodes of paroxysmal hypoxic spells ("tet spells") or could be asymptomatic. In patients who have these episodes, treatment with a beta-adrenoceptor (betaAR) blocking agent can often ameliorate or attenuate the severity of the symptoms. Additionally, excitement, crying, and situations associated with increased sympathetic activity could provoke the occurrence of these hypoxic spells. We hypothesized that altered myocardial betaAR function may contribute to the development of paroxysmal hypoxic spells in the symptomatic tetralogy patient. Surgically excised right ventricular infundibular myocardial specimens from symptomatic (patients with spells) and asymptomatic patients were used to determine total beta1 and beta2 betaAR density and betaAR adenylyl cyclase activity. Symptomatic patients had a significantly greater number of total betaAR. The relative proportion of beta1 and beta2 receptors was comparable in both patient groups. betaAR-stimulated adenylyl cyclase activity was found to be more enhanced in the symptomatic patient group. Our results indicate that infundibular betaARs may play a role in the development of paroxysmal hypoxic spells.

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.

Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the beta-adrenergic receptor (beta AR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the beta AR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery. 5 wk later, after ameroid closure, flow and function were normal in the ischemic bed, but flow (P = 0.001) and function (P < 0.03) were abnormal when metabolic demands were increased. The ischemic bed showed a reduction in myocardial beta AR number (P < 0.005). Despite regional downregulation of myocardial beta AR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Gi alpha 2, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gs alpha, was increased in endocardial sections from the ischemic bed (P = < 0.05). Decreased Gi alpha 2 content was associated with decreased inhibition of adenylyl cyclase. Reduced Gi alpha 2 content, in conjunction with increased Gs alpha content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia.

Adaptations of myocardial beta-adrenergic receptor complex in hibernating marmots

Properties of marmot (Marmota flaviventris) myocardial beta-adrenergic receptor complex (beta-AR) were evaluated during hibernation (H), in summer (S) animals, and in animals aroused from hibernation (C). The results obtained for S and C animals were identical, and only the results for C animals are shown. In H-animal myocardial membrane preparations assayed at 37 degrees C, isoproterenol-dependent adenylate cyclase activity (ACA) was consistently higher, whereas the synergistic contribution of 5'-guanylylimidodiphosphate [Gpp(NH)p] in this reaction was reduced. When assayed at 10 degrees C, only the ACA in H animals responded to the combination of isoproterenol and Gpp(NH)p. In contrast, at 10 degrees C, ACA in response to Gpp(NH)p alone is essentially equal in H and C animals. Hibernation did not change myocardial beta-AR receptor density or affinity. In contrast, analysis of isoproterenol displacement of [125I]iodocyanopindolol revealed that the proportion of beta-AR in the high-affinity state was substantially greater in H than in C animals, and this relationship was retained even in the presence of Gpp-(NH)p. In an evaluation of the role of the GTP binding proteins that couple the beta-AR to the effector adenyl cyclase, we determined that there was no change in the cholera toxin- or pertussis toxin-dependent ADP ribosylation patterns. Immunochemical detection of the individual GTP binding proteins revealed no change in the levels of G alpha i1, G alpha i2, or G alpha i3. In contrast, we observed a hibernation-associated decrease in G alpha o associated with the plasma membrane-enriched particulate fraction. (ABSTRACT TRUNCATED AT 250 WORDS)

Desensitization of myocardial beta-adrenergic receptors during cardiopulmonary bypass. Evidence for early uncoupling and late downregulation.

Cardiopulmonary bypass (CPB), a process routinely used during cardiac surgery, is a potent stimulant to the release of endogenous catecholamines. Hence, we tested the hypothesis that CPB results in myocardial beta-adrenergic receptor (beta AR) desensitization. We obtained canine transmyocardial left ventricular biopsies before, during (155 minutes), and after CPB (pre-CPB, CPB, and post-CPB, respectively) and determined beta AR density, proportion of beta 1AR to beta 2AR, and beta AR coupling capacity to adenylyl cyclase. Beta AR density was stable at 112 +/- 14 fmol/mg (pre-CPB) and 103 +/- 9 fmol/mg (CPB) but decreased post-CPB to 84 +/- 7 fmol/mg. The ratio of beta 1AR to beta 2AR (determined by two-site fit for [125I]-iodocyanopindolol competition binding with the beta 1AR selective antagonist ICI89.406) remained constant throughout (60 +/- 3: 40 +/- 3 pre-CPB, 55 +/- 3: 44 +/- 3 CPB, and 61 +/- 2: 39 +/- 2 post-CPB), revealing that both beta 1AR and beta 2AR subtypes were downregulated. A different pattern was noted in the functional properties of these receptors during CPB. Decreased maximal isoproterenol-stimulated adenylyl cyclase activity (252 +/- 14 to 216 +/- 12 pmol/30 min/mg), submaximal isoproterenol-stimulated adenylyl cyclase activity (183 +/- 10 to 157 +/- 11 pmol/30 min/mg), and zinterol-stimulated adenylyl cyclase activity (187 +/- 11 to 159 +/- 11 pmol/30 min/mg, a measure of beta 2AR subtype activation) were noted during CPB, at the time when weaning from CPB takes place. However, this desensitized pattern was found to be completely reversed by 30 minutes post-CPB, with adenylyl cyclase activities returning to pre-CPB levels or slightly higher. Control dogs that did not receive CPB showed no change in beta AR density or adenylyl cyclase activity. These data suggest that myocardial beta AR desensitization does occur during CPB in healthy, nonischemic canine myocardium and that this pattern is reversed 30 minutes after discontinuation of CPB. In addition, a slower process of beta AR downregulation persists after discontinuation of CPB. Because successful weaning from CPB is a critical process during myocardial surgery, these findings have potentially important implications in the management of such patients.