Peripheral injection of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks peripheral CRF- and abdominal surgery-induced delayed gastric emptying in rats.
The effect of the corticotropin-releasing factor (CRF) receptor antagonists astressin and D-Phe CRF(12-41) injected i.v. on CRF-induced delayed gastric emptying (GE) was investigated in conscious rats. Gastric transit was assessed by the recovery of methyl cellulose/phenol red solution 20 min after its intragastric administration. The 55% inhibition of GE induced by CRF (0.6 microgram i.v.) was antagonized by 87 and 100% by i.v. astressin at 3 and 10 microgram, respectively, and by 68 and 64% by i.v. D-Phe CRF(12-41) at 10 and 20 microgram, respectively. CRF (0.6 microgram)-injected intracisternally (i.c.) induced 68% reduction of GE was not modified by i.v. astressin (10 microgram) whereas i.c. astressin (3 or 10 microgram) blocked by 58 and 100%, respectively, i.v. CRF inhibitory action. Abdominal surgery with cecal manipulation reduced GE to 7.1 +/- 3.1 and 27.5 +/- 3.3% at 30 and 180 min postsurgery, respectively, compared with 40.3 +/- 4.3 and 59.5 +/- 2.9% at similar times after anesthesia alone. Astressin (3 microgram i.v.) completely and D-Phe CRF(12-41) (20 microgram i.v.) partially (60%) blocked surgery-induced gastric stasis observed at 30 or 180 min. The CRF antagonists alone (i.v. or i.c.) had no effect on basal GE. These data indicate that CRF acts in the brain and periphery to inhibit GE through receptor-mediated interaction and that peripheral CRF is involved in acute postoperative gastric ileus; astressin is a potent peripheral antagonist of CRF when injected i.v. whereas i.c. doses >/=3 microgram exert dual central and peripheral blockade of CRF action on gastric transit.
Martínez
V
V
CURE: Digestive Diseases Research Center, West Los Angeles Veterans Administration Medical Center, Department of Medicine, Digestive Disease Division, Los Angeles, CA, USA.
Rivier
J
J
Taché
Y
Y
D000818:Animals; D002946:Cisterna Magna; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007267:Injections; D007275:Injections, Intravenous; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000503:physiopathology
D010446:Peptide Fragments; C113202:phenylalanyl corticotropin-releasing factor (12-41); C104416:astressin; D003346:Corticotropin-Releasing Hormone