Stimulation of gastric acid secretion by progesterone metabolites as neuroactive steroids in anesthetized rats

• Published in: Journal of physiology, Paris Vol. 94; no. 2; pp. 111 - 116
• Main Authors: Watanabe, Kazuo, Nagakura, Yukinori, Hiura, Naoko, Tsuchiya, Shizuko, Horie, Syunji
• Format: Journal Article
• Language: English
• Published: France Elsevier Ltd 01.03.2000
• Subjects: 5α-pregnan-3α-ol-20-one; 5β-pregnan-3α-ol-20-one; Anesthesia; Animals; Atropine - pharmacology; GABA A receptor; GABA Antagonists - pharmacology; Gastric Acid - secretion; Male; Muscarinic Agonists - pharmacology; neuroactive steroid; Picrotoxin - pharmacology; Pregnanolone - pharmacology; Progesterone - metabolism; Rats; Rats, Wistar; Receptors, GABA-A - drug effects; Stereoisomerism; Structure-Activity Relationship; Time Factors; Vagotomy; gastric acid secretion; 5α-pregnan-3α-ol-20-one; GABA A receptor; neuroactive steroid; 5β-pregnan-3α-ol-20-one
• ISSN: 0928-4257; 1769-7115
• DOI: 10.1016/S0928-4257(00)00150-9

The effect of neuroactive progesterone metabolites, 5α- and 5β-pregnan-3α-ol-20-one, and their stereoisomers at the 3 C site, 5α- and 5β-pregnan-3β-ol-20-one, on gastric acid secretion was investigated in urethane-anesthetized rats. Both 5α- and 5β-pregnan-3α-ol-20-one dose-dependently (0.3–3 mg.kg –1, i.v.) stimulated gastric acid secretion with an early onset of action. Their potency and efficacy were almost the equivalent of one another. In contrast, their stereoisomers did not have asignificant effect even at 10 mg.kg –1 (i.v.). The 5β-pregnan-3α-ol-20-one (3 mg.kg –1, i.v.)-stimulated gastric acid secretion was remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg.kg –1, i.v.). An antagonist of the GABA A receptor, picrotoxin, at 3 and 6 mg.kg –1 (i.v.), significantly inhibited the 5β-pregnan-3α-ol-20-one (3 mg.kg –1, i.v.)-stimulated gastric acid secretion. These results indicate that naturally occurring neuroactive steroids, 5α- and 5β-pregnan-3α-ol-20-one, stimulate gastric acid secretion in a stereoselective and dose-dependent manner in urethane-anesthetized rats. It is likely that the action of these neuroactive steroids is of central origin and that interaction with GABA A receptors and stimulation of vagal pathway are involved in its mechanism of action.