Effects of Pinacidil and Cromakalim (BRL 34915) On Bladder Function in Rats with Detrusor Instability

Abstract

Normal rats as well as rats with bladder hypertrophy secondary to outflow obstruction were investigated cystometrically before and after administration of the potassium channel openers pinacidil or cromakalim one mg./kg. orally. In normal rats cromakalim decreased micturition pressure by 15 +/- 6%. A diminished micturition pressure was also seen after pinacidil (by 18 +/- 8%) but this did not achieve statistical significance. Further, no clear-cut effects on bladder capacity, residual volume, basal bladder pressure, threshold pressure, bladder compliance or on bladder wall tension were seen in this group of rats neither in the presence of pinacidil nor cromakalim. Rats with bladder hypertrophy exhibited a significant bladder instability during cystometrical investigations. The mean amplitude of the spontaneous bladder contraction exceeded 20 cm. H2O prior to micturition. Administration of pinacidil and cromakalin decreased the spontaneous contractions to 26 +/- 12% and 22 +/- 7%, respectively, of that seen in the absence of the drugs. Furthermore, pinacidil decreased micturition pressure by 61 +/- 12%. Also cromakalim decreased micturition pressure (by 27 +/- 13%) but this effect did not achieve statistical significance. After both pinacidil and cromakalim these rats tended to develop residual urine. In accordance with the results in normal rats pinacidil and cromakalim showed no effects on bladder capacity, basal bladder pressure, threshold pressure, bladder compliance or on bladder wall tension in rats with bladder hypertrophy. The findings of an almost complete disappearance of spontaneous bladder contractions in rats with bladder instability and a remaining voiding ability after administration of pinacidil or cromakalim suggest that potassium channel openers may be a therapeutic alternative in the treatment of bladder instability associated with outflow obstruction.

(−)-(9 S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4 H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. I. In Vitro Characterization

“…Although this observation is consistent with the preclinical efficacy results in animal models (Malmgren et al, 1989), in the absence of placebo-controlled and definitive clinical data, it is thought that cromakalim and subsequent analogs lack sufficient bladder selectivity relative to the vascular effects. Consequently, further clinical proof of principle for KCOs for bladder overactivity mandates a compound with improved selectivity.…”

“…Urinary bladder smooth muscle, unlike arterial smooth muscle, exhibits action potentials and phasic myogenic activity. Previous studies have shown that KCOs can effectively suppress spontaneous contractions in human urinary bladder (Wammack et al, 1994), guinea pig bladder (Fujii et al, 1990;Hashitani et al, 1996), or hypertrophied rat bladder with instability (Malmgren et al, 1989). In the present study, a comparison of the IC 50 values to suppress spontaneous phasic activity showed that A-278637 is 5-to 10-fold more potent compared with both ZD6169 and WAY-133537.…”

Advances in the pharmacological control of the bladder

“…They also depress contractions induced by electrical stimulation, carbachol, and low, but not high external K' concentrations (Anderson, 1993). The KC channel openers were particularly effective in hypertrophic rat bladder muscle in vitro (Malmgren et al 1990) and suppressed bladder hyperactivity in rats with bladder outflow obstruction without affecting bladder emptying (Malmgren et al 1989).…”

The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions.

“…Cromakalim abolishes spontaneous bladder contractions in pigs [5], rats [8] and rabbits [9] with bladder instability, with little change in other urodynamic variables. Cromakalim also lowers blood pressure in pigs when administered in doses that suppress the unstable contractions [5].…”