Nicorandil ameliorates ischaemia‐reperfusion injury in the rat kidney

Abstract

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

Nicorandil, a Katp channel opener, alleviates chronic renal injury by targeting podocytes and macrophages

“…This finding is consistent with the prior experimental studies (17,19), as well as a recent report that nicorandil could reduce proteinuria in hypertensive subjects (8). Our laboratory has recently reported that nicorandil potently reduced urinary albumin excretion in diabetic endothelial NO synthase-deficient mice (20).…”

“…Nicorandil has been recently reported to have benefit in experimental renal disease, including in the renal injury induced by ischemia-reperfusion (17) and glomerulonephritis (19) in the rats. In humans, the pharmacokinetics of nicorandil were examined in healthy volunteers and patients with impaired renal function (4,10,22).…”

Histological Study on Effect of Mesenchymal Stem Cell Therapy on Experimental Renal Injury Induced by Ischemia/Reperfusion in Male Albino Rat

“…Dislodgment and shedding of epithelial cells was evident with accumulation of cellular debris in tubular lumina as well as acidophilic hyaline casts. Similar changes were previously reported by other investigators who demonstrated severe acute tubular damage in kidney sections of the I/R group (27). The influx of neutrophils, macrophages and lymphocytes during reperfusion initiates a cascade of chemokines liberation with the subsequent production of reactive oxygen species and nitric oxide resulting in further tubular damage (28).…”

“…Similar observations were previously reported by researchers who demonstrated the presence of hyaline exudation in the interstitial spaces as well as peritubular congestion (32). Although reperfusion is essential for the survival of ischaemic tissue, there is good evidence that reperfusion itself causes additional cellular injury "reperfusion injury", which has been attributed to the generation of reactive oxygen species (ROS), depletion of ATP, neutrophil infiltration, and membrane lipid alterations, cytoskeletal dysfunction and intracellular Ca 2+ accumulation (27). Meanwhile, statistical analysis proved a significant decrease in the mean area % of affected tubules 72 hrs after induction of injury (IIb) as compared to 24 hrs after induction of injury (IIa).…”

Nicorandil Protects against Ischaemia-Reperfusion Injury in Newborn Rat Kidney

“…These findings suggested that nicorandil has renoprotective effects in either acute or chronic kidney diseases. Just recently, Shimizu et al [10] reported that pretreatment with nicorandil ameliorated IR-induced kidney injury in adult rats by preventing the reduction of K IR 6.2. However, the underlying molecular mechanisms by which nicorandil plays a renoprotective role in renal IRI is elusive.…”