Corticotropin-releasing Factor

Introduction Immunoreactivity similar to that of corticotropin-releasing factor (CRF) is found in regions of the central nervous system that modulate autonomic responses, including gastrointestinal functions. We examined the central nervous system effects of ovine CRF on gastric acid secretion in conscious dogs. Male beagle dogs (11-13 kg) were fitted with chronic intracerebroventricular cannulae and gastric fistulae. Gastric acid secretion in response to intravenously administered gastric secretory stimuli was measured by in vitro titration of gastric juice to pH 7.0 and in response to an intragastric meal by in vivo intragastric titration at pH 5.0. Plasma gastrin was determined by radioimmunoassay. CRF microinjected into the third cerebral ventricle decreased pentagastrin-stimulated gastric acid secretion for 3 h (P < 0.01) dose-dependently (0.2-6.0 nmol kg-'). CRF did not inhibit histamine-stimulated gastric secretion but significantly (P < 0.01) decreased the secretory response after 2-deoxy-D-glucose for 3 h. The gastric inhibitory action of intracerebroventricularly administered CRF on pentagastrinstimulated gastric acid secretion was completely abolished by ganglionic blockade with chlorisondamine. The opioid antagonist, naloxone, and the vasopressin antagonist, 1l-deaminopenicillamine,240--methyl)tyrosine,8-argininel-vasopressin, significantly suppressed the inhibitory effect of CRF on gastric acid secretion stimulated by pentagastrin. In contrast, truncal vagotomy did not prevent the inhibition of gastric acid secretion induced by CRF. CRF (0.2-2.0 nmolk kg-') administered intracerebroventricularly decreased gastric acid secretion stimulated by 200-ml liquid meals containing 8% peptone. CRF did not affect plasma gastrin concentrations. These results indicate that CRF microinjected into the third cerebral ventricle inhibits gastric acid secretion in conscious dogs. CRF-induced inhibition of gastric acid secretion appears to be mediated by the sympathetic nervous system and, in part, by opiate and vasopressindependent mechanisms. A portion of this report was presented at the 85th Annual Meeting of the American Gastroenterological Association, 19-25 May 1984, New Orleans, LA, and has appeared in abstract form (1984. Gastroenterology. 86:1158). Address correspondence to Dr. Brown. Received for publication 1I June 1984 and in revised form 13 November 1984. Corticotropin-releasing factor (CRF)' is a 41-residue peptide isolated from ovine (1) and rat hypothalami (2). The primary structure of human CRF that is identical to the amino acid sequence of rat CRF was derived from the nucleotide sequence of the cloned DNA (3). CRF stimulates the release of ACTH and f3-endorphin in vivo and in vitro (1). Furthermore, the distribution of CRFlike immunoreactivity within the central nervous system suggests that CRF-containing pathways in the brain are involved in the mediation of autonomic responses (4). CRF administered intracerebroventricularly (i.c.v.) to rats results in activation of the sympathetic nervous system resulting in elevated plasma catecholamine and glucose concentrations (5) as well as in increased mean arterial pressure and heart rate (6). CRF also increases oxygen consumption (7) and motor activity in the rat (8) but decreases sexual behavior (9), food intake (10), and gastric acid secretion (1 1). In the dog, CRF administered i.c.v. activates the sympathetic nervous system and increases plasma vasopressin concentrations (12). The aforementioned central nervous system actions of CRF and the recent demonstration that a CRF antagonist diminished the ACTH release normally observed after either stress (13) imply that CRF may be involved in generating integrated endocrine and autonomic responses to stress (14). The purpose of this study was to examine the central nervous system effects of CRF on gastric acid secretion and to study the mechanism(s) of its action in conscious dogs. In particular, we attempted to assess the role of the autonomic nervous system in mediating the biologic actions of CRF on gastric acid secretion.