AJP - Heart and Circulatory Physiology, Vol 250, Issue 5 769-H777, Copyright © 1986 by American Physiological Society
Antagonism of forskolin effects by adenosine in isolated hearts and ventricular myocytes
G. A. West, G. Isenberg and L. Belardinelli
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)
