Endothelin, released from the fundus of the stomach, participates in the regulation of acid secretion

Abstract

Endothelins comprise a family of 21-amino acid peptides that were initially shown to mediate vasoconstriction; three isoforms, ET-1, ET-2, and ET-3, and two receptor subtypes, ET A and ET a, have been identified. Recently, ET-I was localized by immunohistochemistry to rat parietal ceils (Gastro 102:A156, 1995). In the present study, we have used selective endothelin receptor antagonists to examine the role of endogenous ET1 in the regulation of acid secretion. The isolated mouse stomach was luminally perfused with saline and acid secretion measured by titration. Addition of the ET a antagonist, BQ-788 (0.1 pM), for 20-min caused an increase in acid secretion (11 ± 4%; P < 0.05), implying that endogenous endothelin, acting via ET a receptors, inhibits acid secretion. Consistent with this notion, addition of ET-3 (1 pM to 1 ktM), which interacts preferentially with ET a receptors, caused a concentration-dependent decrease in acid secretion. The maximal response occurred at 10 nM (34 ± 3% below basal level; P < 0.01) and the IC5o was 0.2 nM. In contrast, the ET A antagonist, BQ-485 (0.1 pM), had an opposite effect, slightly decreasing acid secretion (5 -+ 1% below basal level; P < 0.05), implying that endogenous endothelin, acting via ET A receptors, stimulates acid secretion. The ability of endogenous ET-1 to interact with both ET a and ET A receptors is exemplified by the effect of exogenous ET-1 on acid secretion. ET-1 (1 pM to 1 pM) caused a concentration-dependent decrease in acid secretion. The maximal response occurred at 100 nM (33 ± 1% below basal level; P < 0.01) and the IC50 was 5 nM. Preincubation with the ET a antagonist converted the decrease in acid secretion elicited by ET-I (10 nM) to a significant increase above basal level (24 ± 3%; P < 0.01). Preincubation with the ET A antagonist augmented the decrease in acid secretion induced by ET-1 from 17 ± 2% to 24 ± 1% below basal level (P < 0.05 for the difference). A combination of ET A and ET a antagonists abolished the acid response to ET-1, restoring it to basal level. We conclude that ET-1, released from parietal cells, exerts dual inhibitory and stimulatory influences on acid secretion. The dominant effect is inhibitory and mediated via the ET a receptor; a coexistent stimulatory effect, mediated via the ET A receptor, is unmasked when the inhibitory pathway is blocked.