title: Demonstration of vasorelaxant activity with an A1-selective adenosine agonist in porcine coronary artery: involvement of potassium channels.
abstract: The vasodilator activity of adenosine has been associated with selective stimulation of A2 receptors. In the present study, the vasorelaxant (VR) activity of an A1-selective agonist, CPA (cyclopentyladenosine), was examined in isolated porcine coronary arterial rings precontracted with prostaglandin F2 alpha and compared to the A2-selective agonist DPMA (N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl] adenosine). DPMA, approximately 13-fold selective for the rat brain A2 receptor, relaxed isolated coronary arterial rings with an EC50 of 0.59 +/- 0.19 microM (n = 23) whereas CPA, 2200-fold selective for the rat brain A1 receptor, was approximately 5-fold less potent with an EC50 of 3.18 +/- 0.6 microM (n = 11). At low concentrations (10-300 nM) CPA caused vasoconstriction, indicative of the A1-selective nature of this agonist. CGS 15943 (100 nM), a nonselective adenosine antagonist, attenuated the VR activity of DPMA and CPA, causing a 9- and 12-fold rightward shift of the dose-response curves, respectively, whereas 8-cyclopentyl-1,3-dipropylxanthine (20 nM), a highly A1-selective blocker, had no such effect. Both adenosine antagonists abolished the vasoconstrictor response of CPA at low concentrations. The contributions of the cyclic GMP pathway to adenosine-induced VR was assessed using an inhibitor of endothelium-dependent relaxing factor (L-nitroarginine). L-nitroarginine had no effect on the EC50 for CPA-induced VR and, marginally, but not significantly, attenuated DPMA effects. Moreover, no elevation in cyclic GMP levels could be observed in tissues stimulated with CPA or DPMA.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Rhône-Poulenc Rorer Central Research, King of Prussia, Pennsylvania.
authors.forename: L A
authors.initials: LA
authors.lastname: Merkel
authors.forename: R W
authors.initials: RW
authors.lastname: Lappe
authors.forename: L M
authors.initials: LM
authors.lastname: Rivera
authors.forename: B F
authors.initials: BF
authors.lastname: Cox
authors.forename: M H
authors.initials: MH
authors.lastname: Perrone
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; D011983:Receptors, Purinergic; D014665:Vasodilator Agents; D014970:Xanthines; C056426:CGS 24012; D009569:Nitric Oxide; C048599:N(6)-cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D006152:Cyclic GMP; D000241:Adenosine; D011188:Potassium