Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure.

Abstract

We used radioligand binding techniques and measurement of beta-agonist-mediated positive inotropic responses in isolated cardiac tissue to examine beta-adrenergic-receptor subpopulations in nonfailing and failing human left and right ventricular myocardium. In tissue derived from 48 human hearts the receptor subtypes identified in nonfailing ventricle by radioligand binding were beta 1 (77%) and beta 2 (23%), with no evidence of an "atypical" beta-adrenergic receptor. In failing left ventricle the beta 1:beta 2 ratio was markedly different, i.e., 60:38. This decrease in the beta 1 proportion and increase in the beta 2 proportion in the failing ventricles were due to a 62%, "selective" down-regulation of the beta 1 subpopulation, with little or no change in beta 2 receptors. In muscle bath experiments in isolated trabeculae derived from nonfailing and failing right ventricles, both beta 1- and beta 2-adrenergic receptors were coupled to a positive inotropic response. In nonfailing myocardium, beta 1 responses predominated, as the selective beta 1 agonist denopamine produced a response that was 66% of the total contractile response of isoproterenol. In heart failure the beta 1 component was markedly decreased, while the beta 2 component was not significantly diminished. Moreover, in heart failure the beta 2 component increased in prominence, as the contractile response to the selective beta 2 agonist zinterol increased from a minority (39%) to a majority (60%) of the total response generated by isoproterenol. We conclude that failing human ventricular myocardium contains a relatively high proportion of beta 2 receptors, due to selective down-regulation of beta 1 receptors. As a result, in the failing human heart the beta 2-receptor subpopulation is a relatively important mediator of inotropic support in response to nonselective beta-agonist stimulation and is available for inotropic stimulation by selective beta 2 agonists.

Desensitization and Selective Down-Regulation of Rat Cardiac β1-Adrenoceptors by Prolonged In Vivo Infusion of T-0509, a β1-Adrenoceptor Full Agonist

“…In explanted human hearts with dilated cardiomyopathy, ;31ARs are significantly and selectively more down-regulated than the r32-subtype (35,36). It is plausible that the increased level of plasma norepinephrine in patients with heart failure (37) selectively stimulates and decreases ,31ARs.…”

Pharmacogenetics of the human beta-adrenergic receptors

“…[77][78][79] These data could be interpreted to mean that ADRB2 polymorphisms might have greater effects in heart failure. 14 In a study of 259 heart failure patients, the…”

Beta-adrenergic pathway in healthy and hypertrophied hearts

“…Cardiac β−adrenergic receptors are predominantly of the β 1 subtype, and the noncardiac ones, such as those of vessels and lungs, are of the β 2 subtype 7 . In humans, the predominant population of ventricular receptors is β 1 ; β 2 corresponds to only 20% 8,9 . The number of β 2 receptors in the atria, sinus and atrioventricular nodes is twice that of the ventricles 10 .…”

“…The number of β 2 receptors in the atria, sinus and atrioventricular nodes is twice that of the ventricles 10 . Although the coupling degree of β receptors to adenylate cyclase via G-protein is four to five times greater in the β 2 subtype [11][12][13] , and their affinity to agonists is 40 to 50 times greater in the subtype β 1 14 , the intensity of response of the β−receptors to the agonist's action is directly proportional to the number of receptors 8 . In the heart, the action of β 1 receptors is inotropic, while the action of β 2 receptors is chronotropic and dromotropic 1,2,8 .…”