Inhibitory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretion in rats

Abstract

We examined the inhibitory effect of DS-4574 (6-(2-cyclohexylethyl)[1,3,4]thiadiazolo[3,2-alpha]-1,2,3- triazolo[4,5-d] pyrimidin-9(3H)-one), a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretion stimulated by several secretagogues in rats. In anesthetized rats with acute gastric fistulas, DS-4574 (50 mg/kg, intraduodenal) significantly inhibited gastric acid secretion induced by both carbachol (50 micrograms/kg, s.c.) and pentagastrin (75 micrograms/kg, s.c.) but not by histamine (2.5 mg/kg, s.c.). In unanesthetized pylorus-ligated rats, DS-4574 (10 and 25 mg/kg, intraduodenal) markedly suppressed increases in gastric acid output and histamine leakage into the gastric juice produced by carbachol (0.1 mg/kg, s.c.) or pentagastrin (1 mg/kg, s.c.). When the relationship between acid output and histamine leakage elicited by carbachol and pentagastrin was assessed, there was a close correlation (r = 0.84) that was highly significant (P < 0.01). In the in vitro study with rat gastric tissues, DS-4574 (10(-7)-10(-5) M) had no effect on the K(+)-dependent ATPase activity or on aminopyrine uptake into mucosal preparations containing parietal cells stimulated by carbachol (10(-5) M), histamine (10(-4) M), or dibutyryl-cyclic AMP (10(-3) M). These results suggest that the effect of DS-4574 may be mediated by inhibition of endogenous histamine from histamine-storing cells in the stomach.