Tachyphylaxis of the ECL‐cell response to PACAP: receptor desensitization and/or depletion of secretory products

Background and purpose: Rat stomach ECL cells secrete histamine and pancreastatin in response to gastrin and pituitary adenylate cyclase‐activating peptide‐27 (PACAP). This study applies microdialysis to explore how ECL cells in situ respond to PACAP and gastrin. Experimental approach: Both peptides were administered by microinfusion into the gastric submucosa. The microdialysate was analysed for histamine and pancreastatin (ECL‐cell markers) and for somatostatin (D‐cell marker). Key results: Microinfusion of PACAP (0.01–0.3 nmol  μ l −1 ) raised microdialysate histamine and pancreastatin dose‐dependently. The response was powerful but short‐lived. The response to gastrin was sustained at all doses tested. It is unlikely that the transient nature of the histamine response to PACAP reflects inadequate histamine synthesis, since the pancreastatin response to PACAP was short‐lived too, and both gastrin and PACAP activated ECL‐cell histidine decarboxylase. Unlike gastrin, PACAP mobilized somatostatin. Co‐infusion of somatostatin abolished the histamine‐mobilizing effect of PACAP. However, pretreatment with the somatostatin receptor type‐2 antagonist (PRL‐2903) did not prolong the histamine response to PACAP, suggesting that mobilization of somatostatin does not explain the transient nature of the response. Repeated administration of 0.1 nmol  μ l −1 of PACAP (1 h infusions, 1 h intervals) failed to induce a second histamine response. Pretreatment with a low dose of PACAP (0.03 nmol  μ l −1 ) abolished the response to a subsequent near‐maximal PACAP challenge (0.3 nmol  μ l −1 ). Conclusion: The transient nature of the histamine response to PACAP reflects desensitization of the PACAP receptor and/or exhaustion of a specific storage compartment that responds to PACAP but not to gastrin. British Journal of Pharmacology (2007) 152 , 240–248; doi: 10.1038/sj.bjp.0707385