INHIBITORY EFFECT OF DS-4574, A MAST-CELL STABILIZER WITH PEPTIDOLEUKOTRIENE RECEPTOR ANTAGONISM, ON GASTRIC-ACID SECRETION IN RATS

We examined the inhibitory effect of DS-4574 yl)[1,3,4]thiadiazolo[3,2 -a]-1,2,3-triazolo[4,5-d] pyrimidin-9(3H)-one), a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretio n stimulated by several secretagogues in rats. In anesthetized rats wi th acute gastric fistulas, DS-4574 (50 mg/kg, intraduodenal) significa ntly inhibited gastric acid secretion induced by both carbachol (50 mu g/kg, s.c.) and pentagastrin (75 mu g/kg, s.c.), but not by histamine (2.5 mg/kg, s.c.). In unanesthetized pylorus-ligated rats, DS-4574 (1 0 and 25 mg/kg, intraduodenal) markedly suppressed increases in gastri c 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 ca rbachol and pentagastrin was assessed, there was a close correlation ( r = 0.84) that was highly significant (P < 0.01). In the in vitro stud y 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 mucosa l 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 inhibit ion of endogenous histamine from histamine-storing cells in the stomac h.