Tricyclic antidepressants and acid secretory response of rabbit gastric cells

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Abstract
Tricyclic antidepressants were tested for their effect on the H2-receptor-mediated changes in cAMP, O2 consumption and acid secretion in [a model system] 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 .mu.M AMT. Imipramine and nortriptyline 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. At relatively high concentrations (250-500 .mu.M), AMT inhibited the increase in cAMP caused by 5 and 100 .mu.M 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 .mu.M). They inhibited acid formation in control cells, in cells stimulated by histamine, carbachol and DBcAMP, and the potentiated response to carbachol plus histamine or DBcAMP. The onset of this inhibition was rapid and adding 5 .mu.M AMT to the cell suspension either together with histamine or after stimulation by histamine caused a rapid decline in aminopyrine accumulation. In rabbit gastric cells tricyclic antidepressants interact with the histamine receptors to inhibit the histamine-induced cAMP production and O2 consumption. These drugs act on at least 1 additional site, which is at a biochemical step distal to both cAMP generation and the intersection between the pathways leading to the potentiated response, to inhibit nonspecifically the accumulation of aminopyrine. Whether this site is the canalicular H-K-ATPase/H+ pump system or some other membranous site remains to be elucidated. [This study has implications for drug therapy of gastric ulcers.].