TACHYKININ NK2 RECEPTORS IN THE HAMSTER URINARY-BLADDER - IN-VITRO AND IN-VIVO CHARACTERIZATION

We have characterized the contractile responses produced by stimulatio n of the tachykinin NK2 receptor in the hamster urinary bladder in vit ro and in vivo. In isolated bladder strips, neurokinin A (NKA, pD(2) 7 .40. E-max 71% of the response to 80 mM KCI) and the synthetic tachyki nin NK2 receptor selective agonist [beta Ala(8)]NKA(4-10) (pD(2) 7.48, E-max 77% of the response to KCl) both induced a concentration-depend ent contraction, whereas the tachykinin NK1 and NK3 receptor selective agonists, [Sar(9)]substance P sulfone and senktide, respectively, pro duced a negligible contractile effect. The bicyclic peptide antagonist s MEN 11420 and MEN 10627 behaved as competitive antagonists of the re sponse to [beta Ala(8)]NKA(4-10) with apparent pK(B) values of 9.3 and 9.7, respectively. Comparable apparent pK(B) values were estimated ag ainst NKA (pK(B) 9.2 and 9.4 for MEN 11420 and MEN 10627, respectively ). Under isovolumetric recording of the intravesical pressure, the nic otinic receptor agonist DMPP (0.6 mu mol/kg i.v.) produced a phasic co ntraction of the hamster bladder in vivo that was abolished by hexamet honium (110 mu mol/kg i.v.) or by surgical ablation of pelvic ganglia. In vive [beta Ala(8)]NKA(4-10) (10 nmol/kg i.v.) induced a tonic-type sustained bladder contraction with superimposed high frequency and sm all amplitude (<12 mmHg) phasic contractions and, in about 70% of case s examined, a few high amplitude (>20 mmHg) phasic contractions. Hexam ethonium abolished the high amplitude phasic contractions, indicating their reflex origin. In animals subjected to the ablation of pelvic ga nglia, the urinary bladder response to [beta Ala(8)]NKA(4-10) was comp arable to that observed after administration of hexamethonium. Moreove r, hexamethonium did not affect the contractile responses to [PAla8]NK A(4-10) in ganglionectomized animals. MEN 10627 and MEN 11420 produced a dose-dependent and long-lasting inhibition of the contractile respo nse to [beta Ala(8)]NKA(4-10): the least effective doses of the two an tagonists were 30 and 3 nmol/kg i.v. for MEN 10627 and MEN 11420, resp ectively. An almost complete and long-lasting inhibition of the respon se to the agonist was produced at doses of 10 and 100 nmol/kg i.v. of MEN 11420 and MEN 10627. In urethane-anaesthetized hamsters the non-st op intravesical infusion of saline (50 mu l/min) produced repetitive m icturition cycles which were abolished by hexamethonium (110 mu mol/kg i.v.) or by surgical removal of the pelvic ganglia. MEN 11420 (100 nm ol/kg) had no significant effect on the volume-evoked micturition refl ex in anaesthetized hamsters. In conclusion, the hamster urinary bladd er is a suitable preparation for studying the action of tachykinin NK2 receptor antagonists in vivo: in this species, the stimulation of tac hykinin NK2 receptors induces bladder contractions. Blockade of tachyk inin NK2 receptors does not appreciably modify the volume-evoked mictu rition reflex in this species.