Desensitization within and between secretagogues of canine gastric acid and pepsin secretion

Two types of desensitization, autodesensitization and cross-desensitization, of gastric secretory responses to cholinergic (bethanechol and vagal excitation) and noncholinergic stimuli (histamine and pentagastrin) were studied in groups of three to six conscious dogs with gastric fistula. Autodesensitization was manifested as fade of both acid and pepsin secretory responses by 10 to 20%/hr from peak output with all stimuli, histamine, pentagastrin and bethanechol. At the end of 4 hr of pentagastrin, 1.5 micrograms/kg X hr, doubling the dose of pentagastrin for 75 min reversed partly the trend of the acid fade, whereas adding an equipotent dose of histamine was much more effective, i.e., pentagastrin does not desensitize the stomach to histamine. When the three stimuli were given in sequence in random order for 2.5, 1.5 and 1.5 hr, respectively, to study cross-desensitization, histamine and pentagastrin reduced markedly the response of the parietal cells to either direct (bethanechol) or indirect (vagal) subsequent cholinergic stimulation. However, the parietal cells unresponsive to bethanechol remained fully responsive to histamine or pentagastrin, i.e., cholinergic stimulation did not desensitize the stomach to noncholinergic stimuli. From present and published data, neither auto- nor cross-desensitization is due to general, e.g. electrolyte and water depletion, or local, e.g. pH or osmolality, homeostatic consequences of secretion or to the drugs used, e.g. fall in blood pressure with histamine, but to cellular events. Inasmuch as the cell unresponsive to one stimulus may respond to another, a working hypothesis involving receptors is presented.