BACKGROUND AND PURPOSENicorandil, an ATP-sensitive potassium (KATP) channel opener and nitric oxide donor, is used in the treatment of angina and acute heart failure. Here we investigated the effects of two KATP channel openers, nicorandil and cromakalim on ischaemia reperfusion (I-R) injury in the kidney. EXPERIMENTAL APPROACHRight nephrectomy was performed in 8-week-old male Sprague-Dawley rats and they were then divided into six groups: control group; I-R, including 30 min of left renal ischaemia followed by 24 h of reperfusion; I-R groups plus nicorandil 3 or 10 mg·kg -1 i.p.; and I-R groups plus cromakalim 100 or 300 mg·kg -1 i.p. After reperfusion, renal function was estimated by serum creatinine (SCr), urinary albumin : creatinine ratio (ACR) and urinary b2-microglobulin (b2-MG). Levels of KATP channel subtypes were investigated by Western blot. Kidney sections were stained for 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine. KEY RESULTSRenal I-R induced significant increases in SCr, ACR and b2-MG levels compared with the control animals. Treatment with KATP channel openers reduced urinary b2-MG levels, raised by I-R. Both KIR6.1 and KIR6.2 channels were expressed. Expression of KIR6.2 channels in the I-R group was lower than in the control group, which was restored to normal by treatment with KATP channel openers. Histologically, severe acute tubular damage was observed in the I-R kidney and this damage was ameliorated by KATP channel openers, dose-dependently. CONCLUSIONS AND IMPLICATIONSATP-sensitive potassium channel openers protected against proximal tubule damage after I-R injury. Nicorandil could represent a powerful additional component in the treatment of patients undergoing partial nephrectomy or renal transplantation. Abbreviations4-HNE, 4-hydroxy-2-nonenal; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; CKD, chronic kidney disease; ELISA, enzyme-linked immunosorbent assay; IPreC, ischaemic preconditioning; I-R, ischaemia-reperfusion; KATP channel, ATP-sensitive potassium channel; OSOM, outer stripe of outer medulla; PAS, periodic acid-Schiff; ROS, reactive oxygen species; b2-MG, b2-microglobulin

What's known on the subject? and What does the study add? Recently, several studies have suggested that detrusor overactivity (DO) is the result of bladder ischaemia. Hypertension could affect pelvic arterial blood flow, resulting in loss of smooth muscle in the bladder with resultant loss of bladder compliance. Spontaneously hypertensive rats are considered a valuable tool for exploring the pathogenesis of DO. Some reports indicate that α1 adrenoceptor antagonists improve chronic ischaemia of the lower urinary tract in patients with LUTS, with concomitant improvement of their symptoms as well as improvement of DO through an increased bladder blood flow (BBF) in the rat with bladder outlet obstruction. However, the mechanism of improvement of silodosin on storage or irritative symptoms is not well investigated and is still unclear. Silodosin prevents hypertension‐related DO in the SHR via several possible mechanisms. One possible mechanism of the efficacy of silodosin to the DO includes the improvement of the BBF. OBJECTIVE To investigate the effect of the α1A selective adrenoceptor antagonist, silodosin, on hypertension‐related detrusor overactivity (DO) and its possible mechanism in spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS Twelve‐week‐old male SHRs received treatment with silodosin (100 µg/kg perorally) once daily for 6 weeks; vehicle‐treated Wistar rats and vehicle‐treated SHRs were used for our study. Six weeks after silodosin treatment, voiding functions were estimated by voiding behaviour and cystometric studies in all groups. The bladder blood flow was measured by the hydrogen clearance method, and tissue levels of nerve growth factor (NGF) and calcitonin gene‐related peptide (CGRP) were measured by enzyme‐linked immunosorbent assay (ELISA). Furthermore, the expressions of α1 adrenoceptor subtype mRNAs in the bladder were investigated by real‐time PCR method. RESULTS The SHRs showed significant increases in blood pressure, micturition frequency and tissue levels of NGF and CGRP in the bladder. Moreover, the SHRs showed significant decreases in bladder blood flow and single voided volume estimated by both voiding behaviour and cystometric studies compared with those in the Wistar rats. Six weeks of treatment with silodosin significantly ameliorated hypertension‐related alterations of these variables with concomitant small changes of blood pressure. The expression levels of α1 adrenoceptor subtype mRNAs in the bladder were similar in all the groups and the rank order was α1A =α1D > α1B in all groups. However, there were no significant differences in the expressions of α1A adrenoceptor mRNAs between any groups. CONCLUSION The data in the present study suggest that silodosin normalizes hypertension‐related DO in SHRs, which could be related to its effect on the increased blood flow in the bladder.

These data indicate that nicorandil prevents hypertension-related bladder dysfunction in the SHR, which may be related to its effect on the increased blood flow in the bladder.

Our data suggest that BP, BBF, and oxidative stress may be responsible for the functional changes in HT-related bladder dysfunction. Olmesartan significantly ameliorated this bladder dysfunction.

Our data suggest that both silodosin and naftopidil improve hypertension-related bladder dysfunction in the SHR, and naftopidil but not silodosin improves urinary frequency in the light-cycle due to inhibition of urine production.