Adrenoceptor sub-type involvement in Ca2+ current stimulation by noradrenaline in human and rabbit atrial myocytes

Abstract

Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca 2+ current (I CaL ) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such I CaL -increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and β-AR antagonists on NA-stimulated atrial I CaL . I CaL was recorded by whole-cell-patch clamp at 37 °C in myocytes isolated enzymatically from atrial tissues from consenting patients undergoing elective cardiac surgery and from rabbits. NA markedly increased human atrial I CaL , maximally by ~ 2.5-fold, with EC 75 310 nM. Propranolol (β 1 + β 2 -AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated I CaL , in human and rabbit. Phentolamine (α 1 + α 2 -AR antagonist, 1 microM) also decreased NA-stimulated I CaL . CGP20712A (β 1 -AR antagonist, 0.3 microM) and prazosin (α 1 -AR antagonist, 0.5 microM) each decreased NA-stimulated I CaL in both species. ICI118551 (β 2 -AR antagonist, 0.1 microM), in the presence of NA + CGP20712A, had no significant effect on I CaL in human atrial myocytes, but increased it in rabbit. Yohimbine (α 2 -AR antagonist, 10 microM), with NA + prazosin, had no significant effect on human or rabbit I CaL . Stimulation of atrial I CaL by NA is mediated, based on AR sub-type antagonist responses, mainly by activating β 1 - and α 1 -ARs in both human and rabbit, with a β 2 -inhibitory contribution evident in rabbit, and negligible α 2 involvement in either species. This improved understanding of AR sub-type contributions to noradrenergic activation of atrial I CaL could help inform future potential optimisation of pharmacological AR-antagonism strategies for inhibiting adrenergic AF.

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