Stimulation of gastric acid secretion by progesterone metabolites as neuroactive steroids in anesthetized rats.
The effect of neuroactive progesterone metabolites, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, and their stereoisomers at the 3 C site, 5alpha- and 5beta-pregnan-3beta-ol-20-one, on gastric acid secretion was investigated in urethane-anesthetized rats. Both 5alpha- and 5beta-pregnan-3alpha-ol-20-one dose-dependently (0.3-3 mg x 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 a significant effect even at 10 mg x kg(-1) (i.v.). The 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion was remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg x kg(-1), i.v.). An antagonist of the GABA(A) receptor, picrotoxin, at 3 and 6 mg x kg(-1) (i.v.), significantly inhibited the 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion. These results indicate that naturally occurring neuroactive steroids, 5alpha- and 5beta-pregnan-3alpha-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.
Watanabe
K
K
Laboratory of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Nagakura
Y
Y
Hiura
N
N
Tsuchiya
S
S
Horie
S
S
D000758:Anesthesia; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014628:Vagotomy
D001285:Atropine; D018756:GABA Antagonists; D018721:Muscarinic Agonists; D010852:Picrotoxin; D011280:Pregnanolone; D011374:Progesterone; D011963:Receptors, GABA-A