A novel role for cholecystokinin: regulation of mesenteric vascular resistance

The aim of this work was to characterize the vasoactive effect of cholecystokinin on mesenteric vasculature. The mesenteric vascular bed of 3-month-old Sprague-Dawley rats was isolated and perfused at constant flow and changes in perfusion pressure monitored. CCK peptides lacked any direct contractile or relaxing effect on the mesenteric smooth muscle. Transmural nerve stimulation (TNS, 200 mA, 0.2 ms, 8 and 16 Hz) elicited an increase in perfusion pressure reflecting contraction of the bed and CCK inhibited neurogenic contractions elicited by 8 and 16 Hz TNS. The inhibition of neurogenic contractions was blocked by the CCK2 receptor (CCK2R) antagonist, L-365,260 (10 and 100 nM), but not by the CCK1R antagonist, SR-27897. The inhibition of neurogenic contractions was reversed by the non-specific NOS inhibitor, L-NAME as well as by the specific nNOS inhibitor, S-methyl-L-thiocitrulline. In whole-mount segments of mesenteric arteries, CCK2R was detected in the adventitia, in nerve terminals, where it co-localized with synaptophysin and nNOS. CCK-8 immunoreactive fibers were also detected. These results suggest that CCK mediates vasodilatation of the mesenteric vascular bed through the release of NO via its presynaptic CCK2R. Our findings provide, for the first time, a neural mechanism by which CCK may increase mesenteric blood flow.