Effects of PGE2, misoprostol, and enprostil on guinea pig enterocyte adenylate cyclase. Clinical implications.
Prostaglandins of the E series (PGE) are known to stimulate intestinal water and electrolyte secretions via the activation of the enterocyte adenylate cyclase. Their methylated synthetic analogs misoprostol and enprostil induced diarrhea in 5-13% of the patients in most clinical studies. In order to elucidate the role of PGE-adenylate cyclase interaction in these phenomena, we studied the stimulation of adenylate cyclase by native prostaglandin E2 (PGE2) and synthetic PGE analogs on isolated guinea pig intestinal epithelial cells. PGE2 stimulation of adenylate cyclase was dose-dependent, reaching a maximum for 3 x 10(-4) M, with an EC50 of 3.7 x 10(-6) M. The Hill analysis of the concentration-response curve gave a straight line, with a slope close to 1. The effect of PGE2 was strictly additive to that of 10(-5) M forskolin, whereas it was decreased in terms of potency by 10(-9) M cholera toxin. Somatostatin-14 markedly inhibited PGE2 stimulation by 37% and 45% with 10(-9) M and 10(-6) M, respectively. The two PGE methylated analogs misoprostol and enprostil were less potent than PGE2 in stimulating adenylate cyclase in our model.(ABSTRACT TRUNCATED AT 250 WORDS)
Pawlotsky
J M
JM
Unité de Recherches de Gastroentérologie, INSERM U.10, Hôpital Bichat, Paris, France.
Ruszniewski
P
P
Reyl-Desmars
F
F
Bourgeois
M
M
Lewin
M J
MJ
D000262:Adenylyl Cyclases / Q000032:analysis / Q000187:drug effects*; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016620:Enprostil / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D016595:Misoprostol / Q000494:pharmacology*
D016595:Misoprostol; D000262:Adenylyl Cyclases; D016620:Enprostil; D015232:Dinoprostone