cGMP Inhibition of Endothelin-Stimulated Inositol Phosphate Production in the Fetal Lamb Pulmonary Artery

Author： Millard S.L. Russell J.A. Morin III F.C. Adolf M.A. Gugino S.F. Steinhorn R.H.

ISSN： 1094-5539

Source： Pulmonary Pharmacology & Therapeutics, Vol.11, Iss.2, 1998-04, pp. : 201-204

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Abstract

Endothelin-1 (ET-1) stimulates inositol phosphate production in vascular smooth muscle. In the present study, interactions between cyclic GMP (cGMP), cyclic AMP (cAMP) and ET-1 in fetal lamb pulmonary arteries were investigated using phosphoinositide hydrolysis studies and tissue bath techniques. ET-1 was found to be a potent vasoconstrictor of these vessels, with an EC₅₀ of 15.8 nM. ET-1 stimulated total inositol phosphate (IP) production; basal IP production was 68 cpm/mg vs. 247 cm/mg with 1 μM ET-1. 8-bromo-cGMP (2 mM) significantly increased the threshold of ET-1 concentration for pulmonary artery contraction, but had no effect on IP production. Zaprinast (a selective type V phosphodiesterase inhibitor, 60 μM) did not affect ET-1-induced contractility or IP production. IBMX (0.5 mM), a non-specific phosphodiesterase inhibitor, inhibited the potent and maximal effects of ET-1 in arterial contraction and decreased ET-1-stimulated IP production by 49%, while forskolin had a lesser effect in the tissue bath and no effect on IP production. Thus, 8-bromo-cGMP and IBMX alter the contractile effects of ET-1 in the fetal pulmonary artery and IBMX also inhibits inositol phosphate production. The cross-talk mechanisms of these agents require further investigation.