NK1 RECEPTORS MEDIATED RELEASE OF 6-KETO-PGF(1-ALPHA) FROM THE EX-VIVO PERFUSED CANINE ILEUM

The purpose of this study was to determine the effects of tachykinins on prostanoid production by the dog ileum and to characterize the tach ykinin receptor(s) responsible for the principal eicosanoid shown to b e released, 6-keto-PGF(1 alpha). Substance P, the selective NK1 recept or agonist [Sar(9),Met(O-2)(11)]substance P and neurokinin A caused co ncentration-dependent production of 6-keto-PGF(1 alpha); neurokinin A was least potent. The s;elective NK2 agonist [Nle(10)]neurokinin A(4-1 0) had no effect. The selective NK1 antagonist CP-96,345 (10(-7) M), b locked 6-keto-PGF(1 alpha) release from substance P (10(-7) M), [Sar(9 ),Met(O-2)(11)]substance P (10(-7) M) and neurokinin A (10(-7) M). Alt hough the putative NK2 antagonist MEN 10207 (10(-7) M) partially block ed the 6-keto-PGF(1 alpha) release induced by neurokinin A (10(-7) M), We conclude that all these peptides acted primarily on NK1 receptors to induce 6-keto-PGF(1 alpha). Additional experiments suggest that a m ajor site of production of 6-keto-PGF(1 alpha) in the canine ileum may be the vasculature, but these experiments do not exclude other source s such as intestinal muscle for this prostanoid. Calcium-free Krebs' s olution partially reduced the release of 6-keto-PGF(1 alpha) to substa nce P (10(-7) M), implying that extracellular calcium helps support ta chykinin-induced production of 6-keto-PGF(1 alpha). Blockade of synthe sis of another vasoactive mediator, endothelium-derived relaxing facto r (nitric oxide), by N-omega-L-arginine methyl ester) did not alter su bstance P-induced release of 6-keto-PGF(1 alpha). Thus, tachykinin-evo ked release of 6-keto-PGF(1 alpha) in the canine ileum is mediated by NK1 receptor and depends in part on extracellular Ca++ but not bn synt hesis of nitric oxide.