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

Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca²⁺ 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 EC₇₅ 310 nM. Propranolol (β₁ + β₂-AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated I_CaL, in human and rabbit. Phentolamine (α₁ + α₂-AR antagonist, 1 microM) also decreased NA-stimulated I_CaL. CGP20712A (β₁-AR antagonist, 0.3 microM) and prazosin (α₁-AR antagonist, 0.5 microM) each decreased NA-stimulated I_CaL in both species. ICI118551 (β₂-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 (α₂-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 β₁- and α₁-ARs in both human and rabbit, with a β₂-inhibitory contribution evident in rabbit, and negligible α₂ 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.