Effect of the potassium channel opener YM934 on the contractile response to electrical field stimulation in pig detrusor smooth muscle.

Abstract

The effect of a potassium channel opener, YM934, on the contractile response to excitatory neurotransmitters was investigated in isolated pig detrusor smooth muscle. Electrical field stimulation (EFS; 5 second trains, 50 V, 0.8 msec. duration), alpha, beta-MeATP (3 x 10(-7) to 10(-5) M.) or carbachol (3 x 10(-8) to 10(-6) M.) produced a contractile response in isolated pig detrusor smooth muscle. The effect of YM934 on the contractile responses was evaluated in comparison with the antagonism of the putative cotransmitters, acetylcholine and ATP. A tetrodotoxin-sensitive, frequency-dependent contractile response to electrical field stimulation was obtained. Atropine (3 x 10(-8) M.) significantly inhibited the contractile response at high frequencies, whereas alpha, beta-MeATP (5 x 10(-6) M.) (desensitizer of P2X-purinoceptors) significantly inhibited the response at low frequencies. YM934 (10(-8) to 10(-7) M.) dose-dependently inhibited the nerve-mediated contractile responses to all frequencies but preferentially at low frequencies, by analogy with alpha, beta-MeATP. A combination of YM934 (3 x 10(-8) M.) and atropine (3 x 10(-8) M.) reduced the response at all frequencies to between 10 and 20% of control, an effect similar to that obtained with alpha, beta-MeATP (5 x 10(-6) M.) and atropine (3 x 10(-8) M.). In addition, YM934 (3 x 10(-8) M.) markedly inhibited the contractile response induced by exogenously applied alpha, beta-MeATP (3 x 10(-7) to 10(-5) M.) but only slightly inhibited the contractile response induced by exogenously applied carbachol (3 x 10(-8) to 10(-6) M.). These results suggest that YM934 may hyperpolarize the membrane of pig detrusor smooth muscle through the opening of ATP-sensitive potassium channels and, as a result, may functionally inhibit the contractile response to purinergic nerve stimulation that elicits the membrane depolarization.