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 protection occurs via calcitoningene-related peptide (CGRP) release from gastric afferent sensory neurons and nitric oxide (NO)-mediated vasodilation. 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 1 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 hCGRP8-37 (0.047 mg/ml, groups 3 and 6) was continuously infused intraarterially (ia) close to the stomach at a rate of 0.034 ml/min for 1 hr via a catheter inserted retrogradely into the splenic artery. Fifteen minutes after the onset of this infusion, the gastric mucosa was topically exposed to neutral saline solution for 15 min, followed by 160 μM capsaicin for 15 min. The mucosa was then injured by a 15-min exposure to either 5 mM acidified 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 transmucosal H+ flux, luminal accumulation of DNA, and histologic grading (0 = no injury to 3 = severe) by an independent observer. Intraarterial infusion of dcl026;-NAME significantly blocked the hyperemic response of topical capsaicin while having minimal effect on bile acid-induced hyperemia. Intraarterial infusion of hCGRP8-37 blocked the capsaicin-induced hyperemic response and blunted the hyperemic response associated with both 5 and 10 mM ATC, although these results were not statistically significant. Inhibition of this capsaicin-induced hyperemic response by dcl026;-NAME and hCGRP8-37 significantly increased mucosal injury caused by 5 and 10 mM ATC. Intraarterial infusion of hCGRP8-37 and dcl026;-NAME significantly 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.