Both beta- and alpha(1)-adrenoceptors mediate the myocardial effects of catecholamines. It is well known that adenosine inhibits beta-dependent effects; however, whether alpha(1)-dependent responses can be similarly modulated is unclear. Accordingly, rat ventricular myocytes were exposed for 25 min to the alpha(1) agonist phenylephrine (2 mu M, in the presence of 1 mu M propranolol) in the absence or presence of adenosine (100 mu M) or the A(1) receptor-selective agonist N-6-cyclopentyladenosine (CPA, 1 mu M). We also investigated the effects of K-ATP blockade with glibenclamide (1 mu M), the protein kinase C inhibitor bisindolylmaleimide (20 nM), and pertussis toxin (300 ng/ml), which uncouples G(i) protein/receptor interaction, and assessed whether effects of adenosine were mimicked by K-ATP activation with either pinacidil or cromakalim (5 mu M). Phenylephrine significantly increased cell shortening by 190% and the Ca2+ transient by 24%, which was abolished by either adenosine or CPA, but not in the presence of the A(1) receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 mu M), and was abolished by pertussis toxin. The effect of adenosine or CPA was reversed by glibenclamide and mimicked by either cromakalim or pinacidil. Bisindolylmaleimide was without effect. The A(2) or A(3) receptor agonists 2-(4-(2-carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenosine and N-6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (1 mu M each), respectively, were without effect. Neither CPA nor adenosine modulated the effect of endothelin-1 (5 nM), which also acts via the phosphoinositide hydrolysis pathway. We conclude that adenosine selectively inhibits alpha(1)-adrenergic-mediated effects in rat ventricular myocytes through a G(i) protein-dependent mechanism involving A(1) receptor and K-ATP activation. Our study further suggests that endogenous adenosine may modulate alpha(1)-mediated effects of catecholamines.
