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Tricyclic antidepressants and acid secretory response of rabbit gastric cells
Abstract:
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)
Insights
Tricyclic antidepressants, like amitriptyline, potently inhibit histamine-stimulated stomach acid secretion and related cellular functions. These drugs act as competitive inhibitors, impacting cAMP generation and oxygen consumption in gastric mucosal cells.
Area of Science:
- Pharmacology
- Gastroenterology
- Cell Biology
Background:
- Histamine is a key mediator of gastric acid secretion via H2 receptors.
- Cyclic AMP (cAMP) and oxygen consumption are crucial cellular responses to histamine stimulation.
- Tricyclic antidepressants (TCAs) are primarily known for their neurological effects.
Purpose of the Study:
- To investigate the effects of TCAs on H2-receptor-mediated cellular functions in gastric mucosal cells.
- To determine the inhibitory mechanisms and potency of TCAs on cAMP generation, oxygen consumption, and acid secretion.
Main Methods:
- Isolated rabbit gastric mucosal cells were used.
- Effects of amitriptyline (AMT), imipramine, and nortriptyline on histamine-induced cAMP production, O2 consumption, and acid secretion (measured by [14C]aminopyrine accumulation) were assessed.
- Dose-response curves and kinetic analyses (Schild regression, Ki values) were performed.
Main Results:
- Amitriptyline competitively inhibited histamine-induced cAMP generation and O2 consumption with a Ki of 0.75 microM.
- Other TCAs also shifted histamine dose-response curves rightward.
- TCAs were potent inhibitors of acid formation (Ki, 1 microM), affecting basal and stimulated secretion.
- Inhibition was rapid and occurred at concentrations of 250-500 microM for prostaglandin E1 and dibutyryl cAMP (DBcAMP) pathways.
Conclusions:
- TCAs exhibit potent inhibitory effects on gastric acid secretion and related cellular processes.
- The mechanism involves competitive inhibition of H2-receptor-mediated signaling pathways.
- These findings suggest potential gastrointestinal effects of TCAs beyond their psychiatric use.