RT Journal Article
SR Electronic
T1 Inhibition of α<sub>1</sub>-Adrenergic-Mediated Responses in Rat Ventricular Myocytes by Adenosine A<sub>1</sub> Receptor Activation: Role of the K<sub>ATP</sub> Channel
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 770
OP 777
VO 294
IS 2
A1 Nina Hoque
A1 Michael A. Cook
A1 Morris Karmazyn
YR 2000
UL http://jpet.aspetjournals.org/content/294/2/770.abstract
AB Both β- and α1-adrenoceptors mediate the myocardial effects of catecholamines. It is well known that adenosine inhibits β-dependent effects; however, whether α1-dependent responses can be similarly modulated is unclear. Accordingly, rat ventricular myocytes were exposed for 25 min to the α1agonist phenylephrine (2 μM, in the presence of 1 μM propranolol) in the absence or presence of adenosine (100 μM) or the A1 receptor-selective agonistN6-cyclopentyladenosine (CPA, 1 μM). We also investigated the effects of KATP blockade with glibenclamide (1 μM), the protein kinase C inhibitor bisindolylmaleimide (20 nM), and pertussis toxin (300 ng/ml), which uncouples Gi protein/receptor interaction, and assessed whether effects of adenosine were mimicked by KATPactivation 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 A1receptor-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 A2or A3 receptor agonists 2-(4-(2-carboxyethyl)phenylethylamino)-5′-N-ethylcarboxamidoadenosine andN6-(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 α1-adrenergic-mediated effects in rat ventricular myocytes through a Gi protein-dependent mechanism involving A1 receptor and KATPactivation. Our study further suggests that endogenous adenosine may modulate α1-mediated effects of catecholamines. The American Society for Pharmacology and Experimental Therapeutics