Adenosine A1 and A2 receptor agonists alter cardiac functions and prostacyclin release in the isolated guinea-pig heart.
The actions of the adenosine A1 receptor agonist CCPA (2-chloro-N6-cyclopentyladenosine) and the adenosine A2 receptor agonist CGS 21680 (2-[p-(2-carboxyethyl(phenethylamino]-5'-N- ethylcarboxamidoadenosine) on myocardial functions and prostacyclin release were studied in Langendorff-perfused guinea-pig hearts. In spontaneously beating hearts, perfused at constant pressure, CCPA reduced heart rate and left ventricular actively developed pressure with EC50 values of 54.4 +/- 8.7 nM and 81 +/- 6.2 nM, respectively. The adenosine A1 receptor antagonist PACPX (1,3-dipropyl-8-(2-amino-4-chloro)phenylxanthine, 1 microM) antagonized the effects of CCPA on heart rate and left ventricular actively developed pressure and increased the EC50 values 11-fold and 8-fold, respectively. CGS 21680 caused vasodilatation and doubled the coronary flow rate (EC50 of 5.77 +/- 3 nM). The potent but non-selective adenosine receptor antagonist CGS 15943A (9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo(1,5-c)quinazolin++ +-5-imine, 0.1 microM) caused a shift to the right of the concentration-response curve of CGS 21680 for coronary flow rate and increased the EC50 value 52-fold. In electrically paced hearts, perfused at constant flow rate, CCPA (1-100 nM) and CGS 21680 (10-1000 nM) increased the 6-oxo-prostaglandin F1 alpha release (stable non-enzymatic hydrolysis product of prostacyclin) into the cardiac effluent to a maximum of 170 +/- 16% and 184 +/- 6%, respectively. The effects of CCPA and CGS 21680 on cardiac functions indicate a high selectivity of both agonists for adenosine A1 and A2 receptor subtypes of the isolated guinea-pig heart, respectively. The elevation of 6-oxo-prostaglandin F1 alpha in the effluent of guinea-pig hearts by CCPA and CGS 21680 is possibly independent of stimulation of adenosine receptors on the vascular endothelium.
Felsch
A
A
Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany.
Stöcker
K
K
Borchard
U
U
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D011464:Epoprostenol / Q000378:metabolism*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology
D000959:Antihypertensive Agents; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D014230:Triazoles; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C058394:2-chloro-N(6)cyclopentyladenosine; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; C046379:1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine; D000241:Adenosine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine