Tricyclic antidepressants and acid secretory response of rabbit gastric cells.

Tricyclic antidepressants have been tested for their effect on the H2-receptor-mediated changes in cAMP, O2 consumption, and acid secretion in mucosal cells isolated from rabbit stomach. Amitriptyline (AMT) inhibited the action of histamine on both cAMP generation and O2 consumption in an apparent competitive fashion without altering these parameters in unstimulated cells. The onset of this inhibition was rapid and the time at which the increases in these functions had reached steady state was not changed. The Schild regression line for AMT was close to unity, and its Ki values for cAMP production or O2 consumption were 0.75 microM AMT. Imipramine and nortriptyline also caused a rightward shift in the dose-response curve of histamine-induced cAMP generation. The inhibitory action of AMT was specific to histamine in that AMT neither altered the effect of isobutylmethylxanthine on cAMP and respiration nor inhibited the increase in respiration caused by carbachol. However, at relatively high concentrations (250-500 microM), AMT inhibited the increase in cAMP caused by 5 and 100 microM prostaglandin E1 and inhibited the increase in respiration caused by both dibutyryl cAMP (DBcAMP) and by the combination of DBcAMP plus carbachol. Antidepressant drugs were also very potent inhibitors of acid formation as measured by [14C]aminopyrine accumulation (Ki, 1 microM). They inhibited acid formation in control cells, in cells stimulated by histamine, carbachol, and DBcAMP, and also the potentiated response to carbachol plus histamine or DBcAMP. The onset of this inhibition was also rapid, and adding 5 microM AMT to the cell suspension either together with histamine or after stimulation by histamine caused a rapid decline in aminopyrine accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)