THE ROLE OF CALCITONIN-GENE-RELATED PEPTIDE AND NITRIC-OXIDE IN GASTRIC-MUCOSAL HYPEREMIA AND PROTECTION

It has been suggested that capsaicin-induced hyperemia and mucosal pro tection occurs via calcitonin-gene-related peptide (CGRP) release from gastric afferent sensory neurons and nitric oxide (NO)-mediated vasod ilation. The purpose of this study was to determine whether capsaicin and/or bile acid induced hyperemia is mediated by CGRP and/or NO. Male Sprague-Dawley rats (280-350 g) were anesthetized, and the glandular stomach (blood supply intact) was chambered between two plastic rings. Animals were divided into six groups. Normal saline (groups I and 4), the NO inhibitor N-nitro-L-arginine methyl ester (L-NAME; 3.75 mg/ml, groups 2 and 5), or the CGRP antagonist hCGRP(8-37) (0.047 mg/ml, gro ups 3 and 6) was continuously infused intraarterially (ia) close to th e stomach at a rate of 0.034 ml/min for 1 hr via a catheter inserted r etrogradely into the splenic artery. Fifteen minutes after the onset o f this infusion, the gastric mucosa was topically exposed to neutral s aline solution for 15 min, followed by 160 mu M capsaicin for 15 min. The mucosa was then injured by a 15-min exposure to either 5 mM acidif ied taurocholate (ATC, pH 1.2) in groups 1-3 or 10 mM ATC in groups 4- 6. Gastric mucosal blood flow (ml/min/100 g) was continuously measured (laser doppler), and injury was assessed by measuring net transmucosa l H+ flux, luminal accumulation of DNA, and histologic grading (0 = no injury to 3 = severe) by an independent observer. Intraarterial infus ion of L-NAME significantly blocked the hyperemic response of topical capsaicin while having minimal effect on bile acid-induced hyperemia. Intraarterial infusion of hCGRP(8-37) blocked the capsaicin-induced hy peremic response and blunted the hyperemic response associated with bo th 5 and 10 mM ATC, although these results were not statistically sign ificant. Inhibition of this capsaicin-induced hyperemic response by L- NAME and hCGRP(8-37) significantly increased mucosal injury caused by 5 and 10 mM ATC. Intraarterial infusion of hCGRP and L-NAME significan tly inhibit capsaicin-induced hyperemia and protection. In conclusion, capsaicin-induced hyperemia and protection are CGRP and NO dependent. Bile-acid-induced hyperemia, on the other hand, is independent of NO, but may be dependent on CGRP. (C) 1995 Academic Press, Inc.