Effects of endothelin-1 on duodenal bicarbonate secretion and mucosal integrity in rats.
Effects of endothelin-1 on gastric acid secretion, duodenal HCO3- secretion, and duodenal mucosal integrity were investigated in anesthetized rats, in comparison with those of TY-10957, a stable analogue of prostacyclin. A rat stomach mounted on an ex-vivo chamber or a proximal duodenal loop was perfused with saline, and gastric acid or duodenal HCO3- secretion was measured using a pH-stat method and by adding 100 mM NaOH or 10 mM HCl, respectively. Duodenal lesions were induced by mepirizole (200 mg/kg) given subcutaneously. Intravenous administration of endothelin-1 (0.6 and 1 nmol/kg) caused an increase of duodenal HCO3- secretion with concomitant elevation of blood pressure; this effect was antagonized by co-administrahon of BQ-123 (ET(A) antagonist; 3 mg/kg, i.v.) and significantly mitigated by vagotomy. Likewise, endothelin-1 caused a significant decrease in histamine-stimulated acid secretion, and this effect was also significantly antagonized by BQ-123. Although TY-10957 (10 and 30 mg/kg, i.v.) produced a temporal decrease of blood pressure, this agent caused not only an increase of duodenal HCO3- secretion, independent of vagal nerves, but also a decrease of acid secretion as well. In addition, both endothelin-1 and TY-10957 significantly prevented mepirizole-induced duodenal lesions at the doses that caused an increase of duodenal HCO3- secretion and a decrease of gastric acid secretion. These results suggest that endothelin-1 affects the duodenal mucosal integrity by modifying both gastric acid and duodenal HCO3- secretions, the effects being mediated by ET(A) receptors.
Takeuchi
K
K
Department of pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan. takeuchi@mb.kyoto-phu.ac.jp
Sugamoto
S
S
Suzuki
K
K
Kawauchi
S
S
Furukawa
O
O
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism*; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000494:pharmacology*; D004840:Epirizole; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014628:Vagotomy
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D000959:Antihypertensive Agents; D001639:Bicarbonates; D019332:Endothelin-1; D010456:Peptides, Cyclic; C064521:TY 10957; D004840:Epirizole; D011464:Epoprostenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu)