Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium.
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.
Bristow
M R
MR
Department of Medicine, University of Utah School of Medicine, Salt Lake City 84132.
Hershberger
R E
RE
Port
J D
JD
Minobe
W
W
Rasmussen
R
R
D000262:Adenylyl Cyclases / Q000032:analysis*; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D002303:Cardiac Output, Low / Q000201:enzymology*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C026777:ICI 118551; C002904:zinterol; D000262:Adenylyl Cyclases; C037293:denopamine