Antagonism of substance P and related peptides by RP 67580 and CP-96,345, at tachykinin NK 1 receptor sites, in the rat urinary bladder

Abstract

Tonic contraction of rat urinary bladder was elicited in vitro and in vivo by substance P, two selective NK 1 receptor agonists, septide ([pGlu 6, Pro 9]substance P-(6–11)) and [Sar 9, Met(O 2) 11]substance P, and an NK 2 agonist, [Lys 5, MeLeu 9, N Nle 10]neurokinin A-(4–10), but not by senktide (succinyl[Asp 6, MePhe 8]substance P-(6–11)), an NK 3 agonist. Substance P only stimulated the NK 1 receptors of smooth muscle. The non-peptide selective NK 1 receptor antagonists, RP 67580 and CP-96,345, both inhibited substance P-induced contraction (pK B values 6.7 and 5.7; ED 50=1.4 and 5.0 mg/kg i.v., respectively) and septide-induced contraction (pK B values 7.5 and 6.5; ED 50=0.076 and 0.250 mg/kg i.v., respectively). Both antagonists, at lower doses, also inhibited substance P- and septide-induced plasma extravasation. That both antagonists blocked the effects of septide much more than the effects of substance P suggests the existence of an NK 1 receptor subtype or isoform. Selective NK 1 receptor antagonists, by blocking both spasm and plasma extravasation in the urinary bladder, would be useful for treating substance P-related motor disorders and cystitis.