Vol. 294, Issue 2, 770-777, August 2000

Inhibition of ₁-Adrenergic-Mediated Responses in Rat Ventricular Myocytes by Adenosine A₁ Receptor Activation: Role of the K_ATP Channel¹

Nina Hoque, Michael A. Cook and Morris Karmazyn

Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada

Both - and ₁-adrenoceptors mediate the myocardial effects of catecholamines. It is well known that adenosine inhibits -dependent effects; however, whether ₁-dependent responses can be similarly modulated is unclear. Accordingly, rat ventricular myocytes were exposed for 25 min to the ₁ agonist phenylephrine (2 µM, in the presence of 1 µM propranolol) in the absence or presence of adenosine (100 µM) or the A₁ receptor-selective agonist N⁶-cyclopentyladenosine (CPA, 1 µM). We also investigated the effects of K_ATP blockade with glibenclamide (1 µM), 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 µM). 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 A₁ receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 µM), 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 A₂ or A₃ receptor agonists 2-(4-(2-carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenosine and N⁶-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (1 µM 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 ₁-adrenergic-mediated effects in rat ventricular myocytes through a G_i protein-dependent mechanism involving A₁ receptor and K_ATP activation. Our study further suggests that endogenous adenosine may modulate ₁-mediated effects of catecholamines.