Forskolin potentiates the coronary vasoactivity of adenosine in the open-chest dog.
Forskolin, a plant diterpene, directly stimulates adenylate cyclase and also potentiates receptor-mediated stimulation of this enzyme by many stimulatory--but not inhibitory--agonists. We exploited the potentiating effect of forskolin to test the hypothesis that adenosine initiates coronary relaxation through activation of adenylate cyclase. In six open-chest dogs, intracoronary forskolin infusions which produced plasma concentrations between 0.15 and 0.48 microM barely changed coronary flow and had no effect on cardiac performance or oxygen metabolism, and did not cause hypotension. Under these conditions, the EC50 of adenosine, 0.66 microM (range 1.3-2.4), P less than 0.05. In five of the six dogs, higher doses of forskolin, 0.6-6.3 microM, produced the previously described positive inotropic, chronotropic, and systemic hypotensive effects of this drug. These larger doses of the drug increased coronary flow and MVO2 but decreased oxygen extraction, reflecting a combination of direct and metabolic vasodilation. The potentiation of the vasoactivity of adenosine by forskolin supports the hypothesis that the coronary receptor is an adenylate cyclase stimulatory (Ra or A2) receptor.
D000241:Adenosine / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000096:biosynthesis; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005576:Colforsin; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004285:Dogs; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects
D002316:Cardiotonic Agents; D004224:Diterpenes; D011956:Receptors, Cell Surface; D005576:Colforsin; D000262:Adenylyl Cyclases; D000241:Adenosine