The inhibitory effects of different potassium channel openers (PCOs) on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle were examined. PCOs could be an interesting substance class for treatment of detrusor overactivity. Experiments were performed on muscle strips suspended in a tissue bath. Human tissue originated from patients who underwent total cystectomy. The concentration-relaxation curves of the first-generation PCOs cromakalim and pinacidil and the untypical PCO minoxidil were performed using carbachol-precontracted detrusor muscle strips of pigs and humans. Additionally, the inhibitory effects of cromakalim, pinacidil and minoxidil on electrically generated contractions of porcine detrusor muscle were examined. Furthermore, the inhibitory effect of the second-generation, bladder-selective PCO ZM 226600 on electrically generated contractions of the human detrusor muscle was determined. Frequency-response curves were performed before and after incubation with one PCO used in two different concentrations. In humans, cromakalim and pinacidil led to a maximum decrease of 73.5 and 68.4% and showed mean pD2 values of 6.65 and 5.5, respectively. In pigs, cromakalim and pinacidil led to a maximum decrease of 90.6 and 93.6% and showed mean pD2 values of 6.39 and 5.01, respectively. Minoxidil did not significantly decrease the precontraction at the highest used concentration in both species. Cromakalim exhibited the biggest inhibitory effect being significant at 10(-5) and 10(-6) M. Pinacidil showed only a significant inhibitory effect at 10(-5) M which was smaller than that of cromakalim. At 3 x 10(-6) M only a very small effect occurred at 1 Hz. Minoxidil did not inhibit the contractions at both examined concentrations except for a very small effect at 1 Hz. In humans, ZM 226600 exhibited at 10(-6) and 10(-5) M a significant inhibitory effect. At 10(-7) M it was only significant at one frequency.
AimsATP-sensitive potassium channels represent promising drug targets for treating specific bladder diseases. The inhibitory effects of ATP-selective potassium channel openers (PCOs) on the carbachol–response curve in porcine detrusor muscle were examined.Materials and methodsEach of the three substances used in the study represent one prototype of a different class of PCO: cromakalim belongs to the benzopyran series, pinacidil is a cyanoguanidine derivative, and minoxidil represents a pyrimidine derivative. The porcine detrusor muscle represents one of the best models for human detrusor. Experiments were conducted on muscle strips of porcine detrusor muscle suspended in a tissue bath. Concentration–response curves of carbachol were constructed after pretreatment with cromakalim at 10−7, 10−6 and 10−5 M, and with pinacidil and minoxidil at 10−6, 10−5.5 and 10−5 M, respectively. Each muscle strip was only used to examine one concentration of one substance.ResultsCromakalim had the greatest inhibitory effect, significantly suppressing the carbachol–response curve at 10−6 and 10−5 M. Pinacidil showed a significant inhibitory effect at 10−5.5 and 10−5 M, which was smaller than that of cromakalim. Minoxidil did not significantly inhibit the contractions at all examined concentrations.ConclusionsThe examined ATP-sensitive PCOs belonging to the benzopyrans and cyanoguanidines significantly suppressed detrusor contractions. The development of derivatives of these prototypes could open new possibilities for the pharmacological treatment of selected bladder diseases.
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