PGE2 and PGI2 inhibit ET-1 secretion from endothelial cells by stimulating particulate guanylate cyclase.
Prostaglandins (PG)E2 and prostacyclin (PGI2) can cause vasodilation in selective vascular beds and could act in part by inhibiting the production of the vasoconstrictor endothelin-1 (ET-1). We recently reported that these prostanoids inhibit ET-1 production/secretion from cultured endothelial cells via the generation of guanosine 3'-5'-cyclic monophosphate (cGMP). It is unclear whether this results from the stimulation of the particulate (membrane) of soluble (cytosolic) form of guanylate cyclase, and whether these effects are through an intermediate, such as nitric oxide. PGE2 and PGI2 each caused a three- to fourfold increase in both membrane and whole bovine aortic endothelial cell guanylate cyclase activity. The stimulations were significantly reversed (80-90%) by the compound LY-83583, an antagonist to cGMP generation, but were unaffected by methylene blue (MB), an inhibitor of nitric oxide-induced soluble guanylate cyclase. In contrast, the prostaglandins did not generate cGMP in cytosolic fractions. The prostaglandins inhibited ET-1 secretion from the intact cells, which was significantly prevented by LY-83583, but not by MB. Neither prostaglandin stimulated NO synthase activity, an indicator of nitric oxide generation. We conclude that PGE2 and PGI2 are likely to inhibit ET-1 secretion through the activation of the particulate guanylate cyclase, identifying a novel mechanism by which the prostanoids signal in the endothelial cell.
Razandi
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M
Department of Medicine, University of California, Irvine 92717, USA.
Pedram
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A
Rubin
T
T
Levin
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ER
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D006152:Cyclic GMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000494:pharmacology*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D011464:Epoprostenol / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism
D000634:Aminoquinolines; D019332:Endothelin-1; C041715:6-anilino-5,8-quinolinedione; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D015232:Dinoprostone