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

Tonic contraction of rat urinary bladder was elicited in vitro and in vivo by substance P, two selective NK sub(1) receptor agonists, septide ([pGlu super(6),Pro super(9)]substance P-(6-11)) and [Sar super(9), Met(O sub(2)) super(11)]substance P, and an NK sub(2) agonist, [Lys super(5),MeLeu super(9),Nle super(10)]neurokinin A-(4-10), but not by senktide (succinyl[Asp super(6), MePhe super(8)]substance P-(6-11)), an NK sub(3) agonist. Substance P only stimulated the NK sub(1) receptors of smooth muscle. The non-peptide selective NK sub(1) receptor antagonists, RP 67580 and CP-96,345, both inhibited substance P-induced contraction (pK sub(B) values 6.7 and 5.7; ED sub(50) = 1.4 and 5.0 mg/kg i.v., respectively) and septide-induced contraction (pK sub(B) values 7.5 and 6.5; ED sub(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 sub(1) receptor subtype or isoform. Selective NK sub(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.