Effects of KRN2391, a novel vasodilator acting as a nitrate and a K + channel opener, on the rabbit lower urinary tract

Abstract

1. 1. The relaxant effect of KRN2391, suggested to act both as a nitrate and a K + channel opener, was investigated in the rabbit lower urinary tract and compared with the effects of the NO-donor SIN-1 and the K + channel opener levcromakalim. 2. 2. KRN2391 10 −4 M was able to relax precontracted urethral preparations by 87 ± 4%. Corresponding values for levcromakalim 10 −4 M and SIN-1 10 −4 M were 58 ± 8% and 103 ± 2%, respectively. The -logEC 50 values for KRN2391, SIN-1 and levcromakalim were 6.0 ± 0.1, 4.9 ± 0.2 and 5.8 ± 0.2. The relaxant effect of KRN2391 on the bladder was small (29 ± 3%). 3. 3. The levels of cyclic GMP in the urethral preparations were significantly increased after administration of KRN2391 10 −4 M and SIN-1 10 −4 M, but not after levcromakalim 10 −4 M, the levels measured being 9.9 ± 2.2, 20.9 ± 5.1, and 5.2 ± 1.0, compared to the control value, 3.7 ± 0.5 pmol/mg protein. The levels of cyclic AMP were, however, not changed. 4. 4. The relaxations, caused by KRN2391 in the urethral preparations, were accompanied by a hyperpolarization (14 ± 4 mV) of the membrane potential. 5. 5. Methylene blue 3 × 10 −5 M and glibenclamide 10 −5 M significantly reduced the relaxant effect of KRN2391 in the urethral smooth muscle. 6. 6. We suggest that in the rabbit lower urinary tract, KRN2391 acts mainly as an NO-donor.