Nitrovasodilators inhibit thrombin-induced platelet-activating factor synthesis in human endothelial cells.
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 thrombin-elicited 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.
Heller
R
R
Department of Pathological Biochemistry, Medical Academy, Erfurt, Federal Republic of Germany.
Bussolino
F
F
Ghigo
D
D
Garbarino
G
G
Pescarmona
G
G
Till
U
U
Bosia
A
A
D000123:Acetyltransferases / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D010972:Platelet Activating Factor; D009599:Nitroprusside; C016276:8-bromocyclic GMP; C002385:linsidomine; D008981:Molsidomine; D000123:Acetyltransferases; D013917:Thrombin; D006152:Cyclic GMP