Effects of KRN2391, a novel vasodilator acting as a nitrate and a K+ channel opener, on the rabbit lower urinary tract.
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. 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 -logEC50 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. 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. 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 significantly reduced the relaxant effect of KRN2391 in the urethral smooth muscle. 6. We suggest that in the rabbit lower urinary tract, KRN2391 acts mainly as an NO-donor.
Waldeck
K
K
Department of Clinical Pharmacology, Lund University Hospital, Sweden.
Persson
K
K
Andersson
K E
KE
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D006152:Cyclic GMP / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D014521:Urethra / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D007004:Hypoglycemic Agents; D011725:Pyridines; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; C002385:linsidomine; D008981:Molsidomine; D006152:Cyclic GMP