Alpha 1- and beta-adrenergic interactions on L-type calcium current in cardiac myocytes.
We investigated the mechanism by which alpha 1-adrenergic activation regulates basal and stimulated whole cell L-type Ca current (ICa) in rat ventricular myocytes using the physiological neurotransmitter, norepinephrine (NE, 10 microM). Stimulation of alpha 1-adrenoceptors, achieved by NE + 10 microM esmolol (a beta-receptor antagonist), had no significant effect on basal ICa. alpha 1-adrenergic activation had a marked inhibitory effect on ICa elevated by beta activation (NE + 1 microM) prazosin, an alpha 1-receptor antagonist) or activation of adenylyl cyclase by forskolin (25 microM); the inhibitory effect was reversible upon washout. However, alpha 1-adrenergic stimulation had no significant effect on ICa previously increased by intracellular application of cAMP (25 microM). The inhibitory effect seen on ICa elevated by NE showed no significant shift of either I-V or inactivation curves. It is unlikely that the inhibitory effect of alpha 1-adrenergic stimulation on NE or forskolin-elevated ICa is mediated through activation of Ca-dependent protein kinase C or changes in intracellular free Ca (pCa = 8.5, EGTA 5 mM) or cAMP-dependent phosphodiesterase. We conclude that alpha 1-adrenergic inhibition of beta-adrenergic stimulated-ICa is probably mediated through an as yet unknown G-protein. This inhibitory effect could serve as a regulatory feedback mechanism in physiological and pathophysiological settings.
Department of Medicine, State University of New York, Brooklyn.
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Boutjdir
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Restivo
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Wei
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el-Sherif
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D015220:Calcium Channels; D011942:Receptors, Adrenergic, alpha; D009638:Norepinephrine; D011224:Prazosin