Gastric vasodilatation in the rat by cannabinoid (CB) receptor activation: Involvement of sensory neurons and nitric oxide (NO)

Abstract

Background: CB receptors have been implicated in inflammation and pain. CB receptor agonists are potent vasodilators in different vascular preparations, but the mechanism of action is unclear. We investigated the effect of methanandamide, a CB receptor agonist, on the gastric vasculature of the rat stomach in vitro. In particular, we addressed the possibility that methanandamide activated capsaicin-sensitive afferent neurons which are known to release vasoactive substances upon stimulation. Methods: The rat isolated stomach was perfused via the left gastric artery with oxygenated Krebs solution by means of a peristaltic pump. Vasoconstrictor responses were recorded by an increase in intravascular pressure. The lumen of the stomach was filled with 5 ml of saline, gastric contractions being recorded by an increase in intraluminal pressure. The vasculature was precontracted by continuous infusion of methoxamine (10 ILM). Results: Vascular perfusion ofrnethanandarnide (2 or 20 ILM) and capsaicin (0.2 or 2 ILM) caused significant concentration-dependent relaxation of the precontracted va~culature\{lut ha\i no effect on gastric muscle activity. The vasorelaxant activity of n1I:thanandamide was significantly counteracted by the cannabinoid CB t receptor antagonist SR-141716A (l ILM, 30 min, about 50% inhibition) and by L-NAME, an inhibitor of nitric oxide synthase (100 ILM, 30 min, about 30% reduction). The vasorelaxant effect of capsaicin was likewise reduced in the presence of L-NAME (37% reduction) and SR141716A (33% reduction). Neither SR-141716A nor L-NAME exerted any effects per se. Conclusions: Endogenous cannabinoids as well as their receptors are present in the vasculature of the gastrointestinal tract where they are thought to playa role in inflammation and pain. From our data it is conceivable that endogenous cannabinoids activate primary sensory nerve endings in the gastric vasculature and cause vasodilatation via a NO-mediated pathway. Endogenous cannabinoids may thus be pathophysiological stimulants of capsaicin-sensitive afferent neurons that regulate local blood flow and other homeostatic mechanisms of the stomach. Supported by the Austrian Science Foundation (grant P1l834-Med) and the Jubilee Foundation of the Austrian National Bank (grant 7843)