Effects of EDCF and endothelin on phosphatidylinositol hydrolysis and contraction in rat aorta.
Endothelium-derived constricting factor (EDCF) and endothelin are peptidergic substances produced and released from endothelial cells that induce contraction of vascular smooth muscle. The purpose of the present study was to investigate possible mechanisms by which EDCF and endothelin elicit contraction. Exposure of rat aorta to EDCF or synthetic endothelin resulted in time- and concentration-dependent increases in tension and levels of inositol monophosphate, a breakdown product of the phosphatidylinositides. A 10-s exposure to endothelin elevated levels of inositol 1,4,5-trisphosphate. Trypsinization or heating of EDCF prevented the contraction and inositol monophosphate formation. To assess whether EDCF and endothelin may act as endogenous agonists of the dihydropyridine-sensitive Ca2+ channel, we evaluated the ability of the dihydropyridine Ca2+ channel agonist (+)-S202-791 to increase the formation of the inositol phosphates. (+)-S202-791 increased inositol monophosphate formation. However, in contrast to that elicited by EDCF and endothelin, the increase in inositol monophosphate because of (+)-S202-791 was abolished by pretreatment with the cyclooxygenase inhibitor indomethacin (10 microM). These results suggest that contractions induced by EDCFs may be mediated through activation of phospholipase C and subsequent production of second messengers.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio.
R M
RM
Rapoport
K A
KA
Stauderman
R F
RF
Highsmith
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D003470:Culture Media; D004095:Dihydropyridines / Q000494:pharmacology; D016232:Endothelins; D004730:Endothelium, Vascular / Q000502:physiology*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D012965:Sodium Chloride / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D003470:Culture Media; D004095:Dihydropyridines; D016232:Endothelins; D007295:Inositol Phosphates; D010455:Peptides; D010716:Phosphatidylinositols; D014361:Trypsin Inhibitors; D012965:Sodium Chloride; C045796:SAN 202791; D014357:Trypsin; D007213:Indomethacin