Adrenoceptor sub-type involvement in Ca(2+) current stimulation by noradrenaline in human and rabbit atrial myocytes

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.