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


METHODS
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).


RESULTS
Microinfusion of PACAP (0.01-0.3 nmol microl(-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 microl(-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 microl(-1)) abolished the response to a subsequent near-maximal PACAP challenge (0.3 nmol microl(-1)).


CONCLUSIONS
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.
Unit of Cellular and Molecular Pharmacology, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
M
M
Bernsand
R
R
Håkanson
P
P
Norlén
D000818:Animals; D053379:Chromogranin A; D019861:Enterochromaffin-like Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000378:metabolism; D017551:Microdialysis; D010187:Pancreatic Hormones / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors; D013004:Somatostatin / Q000378:metabolism; D013270:Stomach / Q000166:cytology / Q000187:drug effects; D013618:Tachyphylaxis
D053379:Chromogranin A; D005755:Gastrins; C121568:PRL 2903; D010187:Pancreatic Hormones; D010456:Peptides, Cyclic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017481:Receptors, Somatostatin; C115977:Sstr2 protein, rat; C050836:pancreastatin; D013004:Somatostatin; D006632:Histamine; D006640:Histidine Decarboxylase