ANTAGONISM OF SUBSTANCE-P AND RELATED PEPTIDES BY RP-67580 AND CP-96,345, AT TACHYKININ NK1 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 NK1 receptor agonists, septide ([pG lu(6),Pro(9)]substance P-(6-11)) and [Sar(9),Met(O-2)(11)]substance P, and an NK2 agonist, [Lys(5),MeLeu(9),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 NK1 receptors of smooth mus cle. The non-peptide selective NK1 receptor antagonists, RP 67580 and CP-96,345, both inhibited substance P-induced contraction (pK(B) value s 6.7 and 5.7; ED(50)=1.4 and 5.0 mg/kg i.v., respectively) and septid e-induced contraction (pK(B) values 7.5 and 6.5; ED(50)=0.076 and 0.25 0 mg/kg i.v., respectively). Both antagonists, at lower doses, also in hibited substance P- and septide-induced plasma extravasation. That bo th antagzonists blocked the effects of septide much more than the effe cts of substance P suggests the existence of an NK1 receptor subtype o r isoform. Selective NK1 receptor antagonists, by blocking both spasm and plasma extravasation in the urinary bladder, would be useful for t reating substance P-related motor disorders and cystitis.