Antagonism of forskolin effects by adenosine in isolated hearts and ventricular myocytes.
Adenosine is known to antagonize the effects of catecholamine stimulation in atrial and ventricular tissue; however, its mechanism of action is unknown. Forskolin is an inotropic agent that causes an increase in cyclic AMP (cAMP) levels independent of receptor stimulation. We sought to test whether adenosine could attenuate the effects of forskolin in isolated perfused guinea pig hearts and isolated single ventricular myocytes. In isolated perfused hearts (n = 18), forskolin caused a concentration-dependent increase in left ventricular pressure and dP/dt. Adenosine (5 microM) antagonized the forskolin (0.35 microM)-induced increase in left ventricular pressure and dP/dt by 96 +/- 2 and 92 +/- 4% (means +/- SE), respectively. In contrast, in four hearts, adenosine was ineffective in attenuating the inotropic response to dibutyryl cAMP. In isolated ventricular myocytes (n = 10) 150 nM forskolin caused a significant increase in action potential duration and plateau. In voltage-clamp experiments (n = 8), 150 nM forskolin caused a 39 +/- 3% increase in the calcium current, which was antagonized by adenosine (50 microM) by 80%. Forskolin also caused an increase in contractility, as estimated by sarcomere shortening of the cell. Adenosine, and its analogue N6-R-phenylisopropyladenosine (L-PIA), antagonized the effects of 150 nM forskolin on the action potential and on sarcomere shortening. Dibutyryl cAMP had similar effects as forskolin, but they were not antagonized by adenosine. At higher concentrations of forskolin, above 300 nM, delayed after depolarizations and sustained spontaneous activity occurred that could be abolished by L-PIA. Forskolin caused a concentration-dependent increase in cAMP, measured in isolated ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D005576:Colforsin / Q000037:antagonists & inhibitors*; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism
D005576:Colforsin; D000242:Cyclic AMP; D000241:Adenosine