Antagonism of substance P and related peptides by RP 67580 and CP-96,345, at tachykinin NK1 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.