The tachykinin receptors inducing contractile responses of canine ileum circular muscle

Abstract

This study sought to determine which tachykinin receptors were involved in contractile responses of circular muscle to tachykinins infused into isolated segments of canine ileum. Selective agonists for neurokinin receptors NK1 and NK2 as well as for substance P (SP) and neurokinin A (NKA) were infused, and selective antagonists against NK1, NK2, and NK3 receptors were tested. The responses to a submaximal concentration of NKA were reduced by a selective NK2 antagonist, SR-48968, and abolished by a combination of this antagonist with an NK1 antagonist, either CP-96,345 or RP-67580. The selective NK2 agonist, [Nle10]NKA-(4-10), had low potency. We concluded that NKA acted on typical NK2 receptors and that is action was potentiated by its additional action on NK1 receptors. Neither the contractile responses to SP nor those to [Sar9,Met(O2)11]SP given in submaximal concentrations were inhibited by CP-96,345 or RP-67580, either alone or together with SR-48968. Indeed, the two NK1-selective antagonists potentiated responses to the selective NK1 agonist, [Sar9,Met(O2)11]SP, an effect attributed to previously demonstrated prejunctional inhibitory action of the agonist. The selective NK3 agonist, succinyl-[Asp6,N-Me-Phe8]SP-(6-11), was not effective as a contractile agent, even after block of nitric oxide synthase with N omega-nitro-L-arginine. The selective NK3 antagonist, R-487, was also ineffective in blocking responses to SP. Studies with an antagonist to H1 histamine receptors suggested that contractile actions of SP did not involve histamine release from mast cells. We concluded that, in addition to typical NK1 and NK2 receptors activated by NKA and a prejunctional inhibitory receptor activated by SP and [Sar9,Met(O2)11]SP, another tachykinin receptor existed on canine ileum to initiate contractions. It is not a typical NK1, NK2, or NK3 receptor.