Nitric oxide as a regulator of prostacyclin synthesis in cultured rat heart endothelial cells.
The effects of nitric oxide (NO) and its second messenger cyclic guanosine monophosphate (cGMT) on prostacyclin (PGI2) synthesis were studied in cultured rat heart endothelial cells using three different non-enzymatic nitric oxide releasing substances as well as inhibitors of nitric oxide synthase and of soluble guanylate cyclase. Production of prostacyclin, measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), was stimulated up to 1.7 fold in endothelial cells treated with the NO donors SIN-1 (3-morpholino sydnonimine), GEA 3162 (3-aryl-substituted oxatriazole imine) and GEA 3175 (3-aryl-substituted oxatriazole sulfonyl), chloride). In each case the synthesis of cGMP increase as much as 40-100 fold. An inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), decreased the basal production of 6-keto-PGF1 alpha in non-stimulated endothelial cells, an effect that could be reversed by the NO donors SIN-1, GEA 3162 and GEA 3175. cGMP formation in the L-NAME treated endothelial cells was unaltered. The guanylate cyclase inhibitors, methylene blue (100 mumol/l) and LY83583 (100 mumol/l), caused a 1.5-10 fold increase in 6-keto-PGF1 alpha production while NO-donor-stimulated endothelial cGMP production was decreased by 10 to 90%. However, when SIN-1 was used as a stimulant, LY83583 had no significant effect on the production of cGMP. These findings support the hypothesis that NO stimulates prostacyclin production directly by activating cyclooxygenase. The results also suggest that NO could have an indirect effect on prostacyclin production via cGMP.
Sievi
E
E
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Lähteenmäki
T A
TA
Alanko
J
J
Vuorinen
P
P
Vapaatalo
H
H
D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; C093084:GEA 3175; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; D014665:Vasodilator Agents; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; C002385:linsidomine; C082874:GEA 3162; D008981:Molsidomine; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase