Combination of ACE inhibitor with nicorandil provides further protection in chronic kidney disease

• Published in: American journal of physiology. Renal physiology 2014-12, Vol.307 (12), p.F1313-F1322
• Main Authors: Shiraishi, Takeshi, Tamura, Yoshifuru, Taniguchi, Kei, Higaki, Masato, Ueda, Shuko, Shima, Tomoko, Nagura, Michito, Nakagawa, Takahiko, Johnson, Richard J, Uchida, Shunya
• Format: Article
• Language: English
• Subjects: ACE inhibitors; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Antioxidants - pharmacology; Blood Pressure - drug effects; Cell Line; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril - pharmacology; KATP Channels - drug effects; KATP Channels - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney diseases; Male; Mice; Nephrectomy; Nicorandil - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Potassium Channel Blockers - pharmacology; Prescription drugs; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Rodents; Sirtuin 3 - metabolism; Sulfonylurea Receptors - drug effects; Sulfonylurea Receptors - metabolism; Superoxide Dismutase - metabolism; Time Factors
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00521.2014

An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease.