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Am J Physiol Heart Circ Physiol 273: H2380-H2387, 1997;
0363-6135/97 $5.00
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Vol. 273, Issue 5, H2380-H2387, November 1997

A novel phospholipase C- and cAMP-independent positive inotropic mechanism via a P2 purinoceptor

Ernest Podrasky, David Xu, and Bruce T. Liang

Department of Medicine, Cardiovascular Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

Although ATP, acting through a P2 purinoceptor, can stimulate a pronounced positive inotropic effect in cardiac ventricular myocytes, the receptor-effector mechanism that underlies this stimulatory cardiac action is not well understood. The objectives of the present study were to develop the cultured chick embryo ventricular myocytes as a novel model for the cardiac P2 purinoceptor and to determine the mechanism underlying its positive inotropic effect. ATP caused an 89 ± 8.9% (n = 14 cells) increase in the myocyte contractility, with an efficacy and potency order of ATP > ADP > AMP >>  adenosine. 2-Methylthio-ATP (2-MeS-ATP) but not alpha ,beta -methylene-ATP was able to stimulate myocyte contractility, with a maximal increase of 54 ± 2.6% (n = 11 cells). Although UTP potently stimulates phosphoinositide hydrolysis, it had an only modest positive inotropic effect (27 ± 7% maximal increase; n = 8 cells). In contrast to previous suggestions, the 2-MeS-ATP-stimulated positive inotropic response does not require the action of phospholipase C (PLC), such as that of the inositol phosphates; the UTP effect on contractility appears to be mediated via the 2-MeS-ATP-sensitive P2 receptor. The PLC inhibitor U-73122 had no effect on the 2-MeS-ATP-stimulated increase in contractility, providing further evidence against a role for PLC in the inotropic effect of 2-MeS-ATP. An adenosine 3',5'-cyclic monophosphate-independent Ca2+ entry-stimulating mechanism appears to underlie a direct coupling of the receptor to stimulation of the myocyte contractility. This new PLC- and adenosine 3',5'-cyclic monophosphate-independent positive inotropic mechanism represents a target for developing novel positive inotropic therapeutics.

heart; receptor; purinergic; contractility; purines


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