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

American Journal of Physiology - Heart and Circulatory Physiology - Tập 273 Số 5 - Trang H2380-H2387 - 1997
Ernest Podrasky1, David Xu1, Bruce T. Liang1
1Department of Medicine, Cardiovascular Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

Tóm tắt

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 α,β-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.

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American Journal of Physiology - Heart and Circulatory Physiology

Tập 273 Số 5

H2380-H2387

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