Endothelin-1 stimulates phosphatidylinositol hydrolysis and calcium uptake in isolated canine coronary arteries.
The effects of synthetic endothelin-1 (ET-1) (10(-10)-3 x 10(-7) M) on isometric force, 45Ca2+ uptake, and phosphatidylinositol (PI) hydrolysis were determined in isolated canine coronary artery rings. ET-1 caused contraction and stimulated 45Ca2+ uptake and PI hydrolysis (determined as inositol monophosphate accumulation) in a concentration-dependent manner with EC50 values of 6.3 x 10(-9), 2 x 10(-9), and 3 x 10(-9) M, respectively. Maximal responses were obtained with 3 x 10(-8) M ET-1 for all three parameters. At the maximally effective concentration, ET-1 caused a 1.8-fold increase in the rate of 45Ca2+ uptake following a 1-min exposure (the shortest time point tested) while the contractile response reached maximum only after 6 min. ET-1 (3 x 10(-8) M) stimulated a biphasic accumulation of inositol monophosphate with an initial rapid 1.4-fold increase detectable between 30 and 60 s followed by a secondary 11.9-fold increase at 30 min. These data show that PI hydrolysis and Ca2+ uptake are early events in the action of ET-1 on coronary artery vascular smooth muscle that precede the maximal contractile response. It is suggested that all of these responses are triggered by the interaction of ET-1 with a cell-surface receptor.
Pang
D C
DC
Department of Pharmacology, Berlex Laboratories, Inc., Cedar Knolls, New Jersey.
Johns
A
A
Patterson
K
K
Botelho
L H
LH
Rubanyi
G M
GM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D016232:Endothelins; D005260:Female; D006868:Hydrolysis; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D013997:Time Factors
D002132:Calcium Radioisotopes; D016232:Endothelins; D010455:Peptides; D010716:Phosphatidylinositols; D002118:Calcium