β1- and β2-Adrenergic-Receptor Subpopulations in Nonfailing and Failing Human Ventricular Myocardium: Coupling of Both Receptor Subtypes to Muscle Contraction and Selective β1-Receptor Down-Regulation in Heart Failure


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Abstract

We used radioligand binding techniques and measurement of β-agonist-mediated positive inotropic responses in isolated cardiac tissue to examine β-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 β1 (77%) and β2(23%), with no evidence of an “atypical” β-adrenergic receptor. In failing left ventricle the β1: β2 ratio was markedly different, i.e., 60:38. This decrease in the β1 proportion and increase in the β2 proportion in the failing ventricles were due to a 62 %, “selective” down-regulation of the β2 subpopulation, with little or no change in β2 receptors. In muscle bath experiments in isolated trabeculae derived from nonfailing and falling right ventricles, both β1- and β2-adrenergic receptors were coupled to a positive inotropic response. In nonfailing myocardium, β1 responses predominated, as the selective β1 agonist denopamine produced a response that was 66% of the total contractile response of isoproterenol. In heart failure the β1 component was markedly decreased, while the β2 component was not significantly diminished. Moreover, in heart failure the β2 component increased in prominence, as the contractile response to the selective β2 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 β2 receptors, due to selective downregulation of β1 receptors. As a result, in the failing human heart the β2-receptor subpopulation is a relatively important mediator of inotropic support in response to nonselective β-agonist stimulation and is available for inotropic stimulation by selective β2 agonists.

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