l-668169 and senktide

The effects of (+/-) CP 96,345 and L-668,169 on NK1-, NK2- and NK3-receptor mediated contractile responses were compared in guinea-pig and rat isolated smooth muscle tissues. Both (+/-) CP 96,345 and L-668,169 inhibited NK1-mediated responses in guinea-pig ileum (pA2 = 9.3 and 6.4 respectively) but not in rat bladder (pKB = < 6 and < 5.5 respectively) consistent with species differences in NK1-receptor pharmacology. Both compounds showed some selectivity in inhibiting NK1-receptor evoked responses in guinea-pig ileum compared to their inhibitory effects on NK2-receptor mediated responses in guinea-pig bladder and rat ileum and NK3-mediated responses in guinea-pig ileum and rat portal vein.

Topics: Animals; Biphenyl Compounds; Eledoisin; Guinea Pigs; Ileum; Male; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Neurokinin-1 Receptor Antagonists; Organ Specificity; Peptide Fragments; Peptides, Cyclic; Portal Vein; Rats; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Species Specificity; Substance P; Urinary Bladder

Substance P (SP) has been shown to stimulate the hydrolysis of inositol phospholipids in peripheral tissues and in the brain. In mammalian peripheral tissues, three tachykinin receptor subclasses, neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3), have been identified. The purpose of our study was to pharmacologically characterize the SP receptors in the hypothalamus using phosphoinositide breakdown as a functional response. SP, previously described as a NK1 agonist, and Neurokinin A (NKA), previously described as a NK2 agonist, stimulated phosphoinositide breakdown in the hypothalamus in a dose-dependent fashion, with SP being more potent than NKA. The NK2-selective antagonist L-659,877, at a dose of 10(-6) M, abolished the effect of SP (10(-8) M) without affecting basal phosphoinositide breakdown. However, this NK2-selective antagonist did not inhibit the NKA-induced stimulation in phosphoinositide metabolism. The NK1-selective antagonist L-668,169 stimulated phosphoinositide metabolism at a concentration of 10(-6) M, but not at 10(-8) M. This NK1-receptor antagonist did not significantly inhibit the effect of SP on phosphoinositide metabolism. Spantide II, another NK1-selective antagonist, also stimulated phosphoinositide metabolism at a dose of 10(-6) M. Like L-668,169, spantide II failed to inhibit the SP-induced stimulation of phosphoinositide metabolism, and even potentiated the response to SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Carbachol; Dose-Response Relationship, Drug; Hypothalamus; In Vitro Techniques; Inositol; Male; Neurokinin A; Peptide Fragments; Peptides, Cyclic; Phosphatidylinositols; Rats; Rats, Wistar; Receptors, Neurokinin-1; Substance P; Tachykinins