EXCITATORY MOTOR AND ELECTRICAL EFFECTS PRODUCED BY TACHYKININS IN THE HUMAN AND GUINEA-PIG ISOLATED URETER AND GUINEA-PIG RENAL PELVIS

1 In isolated tissue experiments, neurokinin A (NKA) produced concentr ation-dependent contraction of human and guinea-pig ureter (pD(2)=6.7 and 7.2, respectively); an effect greatly reduced (>80% inhibition) by the tachykinin NK2 receptor-selective antagonist MEN 11420 (0.1 mu M) . The tachykinin NK1 and NK3 receptor agonists septide and senktide, r espectively, were ineffective. 2 Electrical field stimulation (EFS) of the guinea-pig isolated renal pelvis produced an inotropic response b locked by MEN 11420 (0.01-1 mu M). In the same preparation MEN 11420 ( 0.1 mu M) blocked (apparent pK(B)=8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor-selective agonist [beta A la(8)]NKA(4-10). 3 In sucrose-gap experiments, EFS evoked action poten tials (APs) accompanied by phasic contractions of human and guinea-pig ureter, which were unaffected by tetrodotoxin or MEN 11420 (3 mu M), but were blocked by nifedipine (1-10 mu M). NKA (1-3 mu M) produced a slow membrane depolarization with superimposed APs and a tonic contrac tion with superimposed phasic contractions. NKA prolonged the duration of EFS-evoked APs and potentiated the accompanying contractions. MEN 11420 completely prevented the responses to NKA in both the human and guinea-pig ureter. 4 Nifedipine (1-10 mu M) suppressed the NKA-evoked APs and phasic contractions in both human and guinea-pig ureter, and s lightly reduced the membrane depolarization induced by NKA. A tonic-ty pe contraction of the human ureter in response to NKA persisted in the presence of nifedipine. 5 In conclusion, tachykinins produce smooth m uscle excitation in both human and guinea-pig ureter by stimulating re ceptors of the NK2 type only. NK1 receptor activation depolarizes the membrane to trigger the firing of APs from latent pacemakers.