BETA-1-ADRENERGIC AND BETA-2-ADRENERGIC RECEPTOR-MEDIATED ADENYLATE-CYCLASE STIMULATION IN NONFAILING AND FAILING HUMAN VENTRICULAR MYOCARDIUM

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  • 1 March 1989
    • journal article
    • research article
    • Vol. 35  (3) , 295-303
Abstract
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 (nonselective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are call 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 .times. 10-9 M), consistent with the .beta.2-receptor Kl of the latter (2.0 .+-. .4 .times. 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 < 0.001) and a .beta.1-receptor density reduced by 61% (p < 0.001), maximal denopamine stimulation was reduced by 49% (p < 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 < 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 < 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.