Effects of PGE2, misoprostol,and enprostil on guinea pig enterocyte adenylate cyclase

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 3×10^–4 M, with an EC₅₀ of 3.7×10^–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. We conclude that (1) the mechanism of PGE₂-mediated intestinal water and electrolyte secretions involves the activation of one single class of specific receptors coupled to enterocyte adenylate cyclase via a cholera toxin-sensitive regulatory subunit (Gs); (2) somatostatin is a potent inhibitor of PGE-stimulated adenylate cyclase and thus could be a interest in the treatment of certain PGE-induced secretory diarrheas; and (3) the diarrheogenic effects of misoprostol and enprostil are unlikely to be mediated primarily by adenylate cyclase activation.