In vitro and in vivo characterization of an A1-selective adenosine agonist, RG14202.
In this report, we demonstrate that the adenosine agonist N-5'-ethyl-N6-(cyclopentyl) adenosine-5'-uronamide (RG14202) is a vasorelaxant in porcine coronary arterial rings (EC50 = 0.37 +/- 0.054 microM; n = 19). This vasorelaxation (VR) occurs despite RG14202 being 275-fold selective for the rat brain A1 receptor. VR in response to RG14202 was attenuated markedly by the nonselective adenosine antagonist CGS15943, whereas 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a highly selective A1 antagonist, had only a small inhibitory effect. In contrast, the potassium channel blocker glybenclamide attenuated RG14202-induced VR markedly (85-fold), indicating that modulation of potassium channels is likely involved. In carotid arterial rings, RG14202 was approximately 5 times less potent than in the coronary artery, suggesting that this compound may be more selective for the coronary vasculature. In anesthetized rats, i.v. administration of RG14202 caused a significant decrease in mean arterial pressure only at the highest dose (3 micrograms/kg). In comparison, heart rate was decreased dose-dependently with maximal changes at 3 micrograms/kg. Both the depressor and bradycardic responses could be antagonized with CGS15943. RG14202 increased renal, but had no effect on mesenteric or hindquarter vascular resistance. Glybenclamide pretreatment (20 mg/kg) did not significantly alter the effects of RG14202 on heart rate or regional vascular resistances; however, the depressor response to RG14202 was attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)
Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania.
L A
LA
Merkel
L M
LM
Rivera
D J
DJ
Colussi
M H
MH
Perrone
G J
GJ
Smits
B F
BF
Cox
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000378:metabolism / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
D003517:Cyclopentanes; D011983:Receptors, Purinergic; C081307:RG 14202; D015237:Dinoprost; D000241:Adenosine; D005905:Glyburide