Cholecystokinin Induces Cerebral Vasodilatation via Presynaptic CCK2 Receptors: New Implications for the Pathophysiology of Panic

Abstract

The authors report that cholecystokinin (CCK), via its subtype 2 receptor (CCK2R) located presynaptically on cerebral arteries, mediates the release of nitric oxide (NO), which induces vasodilatation. Whereas CCK octapeptide and its fragment CCK tetrapeptide (CCK-4) lack a direct effect on the smooth muscle of pial vessels, the authors showed that both CCK peptides modulate the neurogenic responses in bovine cerebral arteries. The neurogenic vasodilatation induced by CCK-4 was blocked by the CCK2R antagonist, L-365,260, and antagonized by neuronal NO synthase (nNOS) inhibitors, but was independent of the endothelium. In whole-mount arteries, CCK2Rs were detected in nerve fibers and colocalized with nNOS and synaptophysin. The findings provide, for the first time, a neural mechanism by which CCK may increase cerebral blood flow.