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To identify the role of the myocardial beta-adrenergic pathway in congestive heart failure, we examined beta-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in beta-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P less than 0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P less than 0.05). We conclude that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction. Regulation of beta-adrenergic receptors may be an important variable in cardiac failure.

We examined alpha-1 adrenergic receptor density in ventricular myocardium from nonfailing and failing human hearts, utilizing the alpha-1 radioligand [125I]IBE2254. The alpha-1 receptor population comprised a relatively small portion of the total adrenergic receptors, 14.6 +/- 1.9%. However, in failing human ventricular myocardium the alpha-1 adrenergic receptor population constituted a much greater portion, 27.3 +/- 2.1% (P less than .01). The reason for the increased proportion of alpha-1 adrenergic receptors was not that the total concentration of alpha-1 receptors was increased, but instead was due to selective down-regulation of the beta-1 adrenergic receptor population. Beta-2 adrenergic receptors behaved similarly to alpha-1 adrenergic receptors in the failing human heart, and were increased in proportion and unchanged in total number. Additionally, the ability of alpha-1 stimulation to increase the incorporation of label from [3H]inositol into inositol phosphates was examined in tissue homogenates. Maximal doses of norepinephrine produced only marginal stimulation of phosphatidylinositol hydrolysis, in contrast to a more substantial response produced by muscarinic stimulation. We conclude that human ventricular myocardium contains alpha-1 adrenergic receptors that 1) are of relatively low density, 2) are unchanged in density by heart failure and 3) mediate relatively low-level stimulation of phosphatidylinositol hydrolysis.

Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.