Nitrovasodilators inhibit thrombin-induced platelet-activating factor synthesis in human endothelial cells

Regine Heller, Federico Bussolino, Dario Ghigo, Giovanni Garbarino, Glanpiero Pescarmona, Uwe Till, Amalia Bosia

Research output: Contribution to journalArticlepeer-review

Abstract

In response to inflammatory agents such as thrombin, cultured endothelial cells produce platelet-activating factor (PAF), which has been linked with most inflammatory and immune processes, and is a potent coronary constrictor. Sodium nitroprusside (SNP) and SIN-1 (3-morpholinosydnonimine), which spontaneously release the free radical nitric oxide (NO), cause direct relaxation of blood vessels and inhibition of platelet aggregation by activating soluble guanylate cyclase. In the present study we report that in human umbilical vein endothelial cells (HUVEC) these compounds stimulate the production of cGMP and inhibit thrombin-induced PAF synthesis in a concentration-dependent manner. 8-bromo-cGMP, a permeant non-hydrolysable analogue of cGMP, mimics the inhibitory effect of NO-generating vasodilators. PAF synthesis requires phospholipase A2-mediated hydrolysis of membrane precursors to lyso-PAF, which is in turn converted into PAF by an acetyltransferase. The thrombinelicited activation of both enzymes is inhibited in a dose-dependent way in HUVEC pretreated with SNP and SIN-1. The inhibitory effect of SNP and SIN-1 on the thrombin-mediated PAF synthesis suggests a new mechanism of action whereby the endogenous NO can affect vascular tone and endothelium-dependent intercellular adhesion. Moreover, PAF production in endothelial cells appears to be an important target for the pharmacological action of nitrovasodilators.

Original languageEnglish
Pages (from-to)223-229
Number of pages7
JournalBiochemical Pharmacology
Volume44
Issue number2
DOIs
Publication statusPublished - Jul 22 1992

ASJC Scopus subject areas

  • Pharmacology

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