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RJ Heaslip and BD Sickels
Division of Immunopharmacology, Wyeth-Ayerst Research, Princeton, New Jersey.
The effects of prostaglandin (PG) F2 alpha and PGB2 on isolated rat aortic strips were studied in calcium-free 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid buffer to explore the mechanisms of PG-induced smooth muscle contraction. In the absence of extracellular calcium, PGF2 alpha and PGB2 induced sustained contractions that were similar to those induced by activators of protein kinase C (PKC) or norepinephrine. These sustained contractions were apparently induced via a pharmacomechanical coupling mechanism because they could be elicited repeatedly in the absence of extracellular calcium and were not affected by changes in buffer concentrations of potassium, magnesium or phosphate. They depended on intracellular but not extracellular calcium because they were reversed by nitroprusside but not by nifedipine, verapamil or diltiazem. Contractions induced by combining either PG with 12-O-tetradecanoyl- phorbol-13-acetate or mezerein were consistent with the suggestion that PG-induced contractions were induced via a PKC-dependent mechanism. Moreover, both PGF2 alpha- and PGB2-induced contractions were inhibited noncompetitively by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine at concentrations known to inhibit PKC but not myosin light chain kinase. These data, combined with those published from other laboratories, suggest that PGF2 alpha and PGB2 induce contraction of the rat aorta, at least in part, by activating PKC. However, PG-induced contractions did not require enhanced phosphoinositide hydrolysis and apparently did not involve the mobilization of intracellular calcium by inositol 1,4,5- trisphosphate. The data thus suggest that PGs activate PKC via a novel mechanism.
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