EFFECTS OF KRN2391, A NOVEL VASODILATOR ACTING AS A NITRATE AND A K-TRACT( CHANNEL OPENER, ON THE RABBIT LOWER URINARY)

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+ c hannel opener levcromakalim. 2. KRN2391 10(-4) M was able to relax pre contracted urethral preparations by 87 +/- 4%. Corresponding values fo r 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 levcro makalim were 6.0 +/- 0.1, 4.9 +/- 0.2 and 5.8 +/- 0.2. The relaxant ef fect of KRN2391 on the bladder was small (29 +/- 3%). 3. The levels of cyclic GMP ih the urethral preparations were significantly increased after administration of KRN2391 10(-4) M and SIN-1 10(-4) M, but not a fter 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. The relaxations, caused by KRN2391 in the urethral preparations, were accompanied by a hyperpolarization (14 +/- 4 mV) of the membrane potential. 5. Methylene blue 3 x 10(-5) M and glibenclamide 10(-5) M s ignificantly reduced the relaxant effect of KRN2391 in the urethral sm ooth muscle. 6. We suggest that in the rabbit lower urinary tract, KRN 2391 acts mainly as an NO-donor.