title: Inhibition of alpha(1)-adrenergic-mediated responses in rat ventricular myocytes by adenosine A(1) receptor activation: role of the K(ATP) channel.
abstract: 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 microM, in the presence of 1 microM propranolol) in the absence or presence of adenosine (100 microM) or the A(1) receptor-selective agonist N(6)-cyclopentyladenosine (CPA, 1 microM). We also investigated the effects of K(ATP) blockade with glibenclamide (1 microM), 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 microM). Phenylephrine significantly increased cell shortening by 190% and the Ca(2+) 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 microM), 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-ethylcarboxamidoade nos ine and N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (1 microM 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Hoque
authors.forename: M A
authors.initials: MA
authors.lastname: Cook
authors.forename: M
authors.initials: M
authors.lastname: Karmazyn
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008301:Maleimides / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D016276:Ventricular Function
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018340:Receptors, Adrenergic, alpha-1; D018047:Receptors, Purinergic P1; D010656:Phenylephrine; C048599:N(6)-cyclopentyladenosine; D000255:Adenosine Triphosphate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000241:Adenosine; C088060:bisindolylmaleimide; D002118:Calcium