The effects of KRN2391 (N-cyano-N'-(nitroxyethyl)-3-pyridine carboximidamide methane-sulfonate), which possesses ATP-sensitive potassium (K+) channel opening (KCO) activity and nitrate activity; Ki1769 (N-cyano-N'-(phenylethyl)-3-pyridinecarboximidamide methanesulfonate), which possesses only KCO activity; and nitroglycerin (NG) were determined on the motility of the ureter, urinary bladder and urethra of rats. Bladder contraction was induced by infusion of fluid into the bladder of conscious rats and recorded on a cystometrogram. KRN2391 and Ki1769 (both 0.3 mg/kg, i.v.) prolonged the micturition interval immediately after the injection, but NG (5 mg/kg, i.v.) did not. Peristaltic movement of the ureter, recorded in anesthetized rats, was inhibited by i.v. injection of KRN2391 and Ki1769 (both 0.03 mg/kg). However, when NG, NaNO2, N-nitro L-arginine methylester and methylene blue were applied directly to the ureter, no change in movement of the ureter was detected. KRN2391 (0.03 mg/kg, i.v.) and Ki1769 (0.3 mg/kg, i.v.) reduced the resistance to fluid infusion through the urethral lumen in anesthetized rats, whereas NG (0.5 mg/kg, i.v.) only reduced this resistance transiently. These results indicate that KCO activity had an inhibitory effect on the motility of the ureter, bladder and urethra. On the other hand, nitrate activity had an inhibitory effect on urethral tonus, corresponding to that induced by KCO activity.

ABSTRACT-We studied the effect of levcromakalim on the function of the urinary tract in rats. Using anesthetized rats, ureteral peristaltic movement of only the ureter region or the ureter with the kidney was in duced by fluid infusion into the ureter lumen. Levcromakalim (0.03 and 0.3 mg/kg, i.v.) exerted a stronger inhibitory effect on the peristaltic movement of the ureter region distant from the pelvis than on that near the pelvis, and the inhibitory effect of levcromakalim (0.03 mg/kg, i.v.) was not antagonized by glibenclamide (0.1 mg/kg, i.v. or 10 mg/kg, i.p.). Topical application of levcromakalim (injection volume, 0.1 ml; 10-4 or 10-3 M), which was injected via a vessel near the ureter inhibited ureteral peristaltic move ment and the inhibitory effect levcromakalim (10-4 M), was not antagonized by glibenclamide (10-'M) in jected via the same route. Levcromakalim (0.3 mg/kg, i.v.) did not interrupt micturition in anesthetized and conscious rats. In conscious rats, the micturition interval was prolonged; and in anesthetized rats, the peak pressure during micturition was reduced. After injection of levcromakalim (0.3 mg/kg, i.v.), vesicoureteral reflux did not occur. In the movements of the ureter, urinary bladder and urethra, levcromakalim exerted the strongest inhibitory effect on the ureteral peristalsis.Keywords: Levcromakalim, Glibenclamide, Ureteral peristaltic function (rat), Cystometrogram, MicturitionCromakalim, a K+ channel opener, exerts relaxant effects in many kinds of smooth-muscle organs by hyper polarizing the membrane through activation of K+ chan nels (1-5), and their clinical usefulness for the treatment of urinary bladder dysfunctions in which the detrusor muscle becomes hyperexcitable is suggested from studies on guinea pigs and rats (4, 6), as well as hypertension (7) and asthma in patients (8). Recently, we reported that lev cromakalim (BRL 38227), which is the (-)enantiomer of cromakalim and has identical properties but can be used at a lower dose level (9), had a strong inhibitory effect on myogenic ureteral peristaltic movement when a solution containing the drug was infused into the ureter lumen in anesthetized rats (10). The lower urinary tract, including the ureter, urinary bladder and urethral proximal sphinc ter, is composed of smooth muscle; and its function of urine transport, storage or evacuation (micturition) is dependent upon the integrated motility of these organs in the lower urinary tract. Therefore, it is of interest to clarify the effect of levcromakalim on the functions of the lower urinary tract. In the present study using rats, lev cromakalim was systemically or topically injected, and its effects on ureteral peristaltic movement and the cysto metrogram were investigated. MATERIALS AND METHODSFor studying the effects of drugs on ureteral peristaltic movement, we used a method that was a partial modifi cation of our system previously used to investigate the effects of drugs applied from the ureter lumen (10). The experimental setup is shown in Fig. 1. Male Sprag...

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