NK1 receptors mediated release of 6-keto-PGF1 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 tachykinin receptor(s) responsible for the principal eicosanoid shown to be released, 6-keto-PGF1 alpha. Substance P, the selective NK1 receptor agonist [Sar9,Met(O2)11]substance P and neurokinin A caused concentration-dependent production of 6-keto-PGF1 alpha; neurokinin A was least potent. The selective NK2 agonist [Nle10]neurokinin A(4-10) had no effect. The selective NK1 antagonist CP-96,345 (10(-7) M), blocked 6-keto-PGF1 alpha release from substance P (10(-7) M), [Sar9,Met(O2)11]substance P (10(-7) M) and neurokinin A (10(-7) M). Although the putative NK2 antagonist MEN 10207 (10(-7) M) partially blocked the 6-keto-PGF1 alpha release induced by neurokinin A (10(-7) M), we conclude that all these peptides acted primarily on NK1 receptors to induce 6-keto-PGF1 alpha. Additional experiments suggest that a major site of production of 6-keto-PGF1 alpha in the canine ileum may be the vasculature, but these experiments do not exclude other sources such as intestinal muscle for this prostanoid. Calcium-free Krebs' solution partially reduced the release of 6-keto-PGF1 alpha to substance P (10(-7) M), implying that extracellular calcium helps support tachykinin-induced production of 6-keto-PGF1 alpha. Blockade of synthesis of another vasoactive mediator, endothelium-derived relaxing factor (nitric oxide), by N omega-L-arginine methyl ester) did not alter substance P-induced release of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Parrish
M B
MB
McMaster University, Division of Physiology and Pharmacology, Hamilton, Ontario, Canada.
Rainsford
K D
KD
Johnson
D M
DM
Daniel
E E
EE
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D007082:Ileum / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011863:Radioimmunoassay; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology
D018040:Receptors, Neurokinin-1; D013373:Substance P; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol