Distortion of H2-antagonist equilibrium constants by uptake in rabbit gastric mucosal cells

In rabbit gastric cells the new H2-antagonists, BL-6341A, SK&F 93479 and L-643,441 were highly potent inhibitors of the H2-receptor mediated action of histamine as monitored by 14C-aminopyrine uptake and cyclic AMP formation. BL-6341A and SK&F 93479 acted as competitive antagonists to histamine and dimaprit but they were less potent against dimaprit (Ki, 8.9 nM) than against histamine (Ki, 3.5-4.4 nM). Furthermore, the Schild slope for L-643,441 against histamine was significantly higher than unity (1.69-1.79), which is inconsistent with competitive antagonism, whereas against dimaprit it was close to unity. In contrast to these antagonists, cimetidine was an equally potent competitive antagonist of both histamine and dimaprit. 3H-histamine was taken up by gastric cells as evidenced by the loss of 60-70% of the cell-associated radioactivity upon hypotonic lysis. These results suggest that uptake and possibly metabolism of histamine by rabbit gastric cells is partially responsible for the distortion of the estimated equilibrium constants for these H2-antagonists.