Abstract
Background
Hypertension is a risk factor common to both chronic kidney disease and cardiovascular disease. Nicorandil is widely used for the treatment of angina. We investigated the benefits of nicorandil with respect to renal dysfunction in Dahl salt-sensitive hypertensive (DS) rats.
Method
DS rats were fed a high-salt (HS) diet and nicorandil was administered via the drinking water. Blood pressure and renal function were measured for 4 weeks after starting the rats on the HS diet.
Results
In rats fed the HS diet, renal dysfunction was manifested by an increase in urinary protein and N-acetyl-β-d-glucosaminidase excretion. Nicorandil ameliorated renal function with a concomitant reduction in urinary 8-hydroxy-2′-deoxyguanosine and an increase in urinary NOx. Significant upregulation of endothelial nitric oxide synthase (eNOS) expression and an increase in the eNOS dimer/monomer ratio (reduction of eNOS uncoupling) was demonstrated in glomeruli following nicorandil treatment. The blood pressure of DS rats was increased by salt loading; however, no significant change in blood pressure was observed with nicorandil treatment.
Conclusion
In DS rats fed a HS diet, nicorandil prevented the development of renal dysfunction, which was accompanied by an increase in eNOS expression in the kidneys.
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References
Hayata M, Kakizoe Y, Uchimura K, Morinaga J, Yamazoe R, Mizumoto T, et al. Effect of a serine protease inhibitor on the progression of chronic renal failure. Am J Physiol Renal Physiol. 2012;303:F1126–35.
Bragulat E, de la Sierra A, Antonio MT, Coca A. Endothelial dysfunction in salt-sensitive essential hypertension. Hypertension. 2001;37:444–8.
Westermann D, Riad A, Richter U, Jäger S, Savvatis K, Schuchardt M, et al. Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol. 2009;104:499–509.
Satoh M, Haruna Y, Fujimoto S, Sasaki T, Kashihara N. Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats. Hypertens Res. 2010;33:135–42.
IONA Study Group. Impact of nicorandil in angina: subgroup analyses. Heart. 2004;90:1427–30.
Ishii H, Toriyama T, Aoyama T, Takahashi H, Yamada S, Kasuga H, et al. Efficacy of oral nicorandil in patients with end-stage renal disease: a retrospective chart review after coronary angioplasty in Japanese patients receiving hemodialysis. Clin Ther. 2007;29:110–22.
Nishimura M, Tokoro T, Nishida M, Hashimoto T, Kobayashi H, Yamazaki S, et al. Clinical potential of nicorandil to inhibit major cardiac events in hemodialysis patients with suspected myocardial ischemia. Nephron Clin Pract. 2009;111:c212–21.
Nishimura M, Tokoro T, Nishida M, Hashimoto T, Kobayashi H, Imai R, et al. Oral nicorandil to reduce cardiac death after coronary revascularization in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2009;54:307–17.
Horinaka S, Kobayashi N, Yagi H, Mori Y, Matsuoka H. Nicorandil but not ISDN upregulates endothelial nitric oxide synthase expression, preventing left ventricular remodeling and degradation of cardiac function in Dahl salt-sensitive hypertensive rats with congestive heart failure. J Cardiovasc Pharmacol. 2006;47:629–35.
Felder RA, Blecher M, Eisner GM, Jose PA. Cortical tubular and glomerular dopamine receptors in the rat kidney. Am J Physiol. 1984;246:F557–68.
Serizawa K, Yogo K, Tashiro Y, Koike N, Aizawa K, Hirata M, et al. Nicorandil ameliorated hypertensive renal injury without lowering blood pressure in spontaneously hypertensive rats. Pharmacology. 2013;91:92–103.
Shimizu S, Saito M, Kinoshita Y, Ohmasa F, Dimitriadis F, Shomori K, et al. Nicorandil ameliorates ischaemia–reperfusion injury in the rat kidney. Br J Pharmacol. 2011;163:272–82.
Tanabe K, Lanaspa MA, Kitagawa W, Rivard CJ, Miyazaki M, Klawitter J, et al. Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse. Am J Physiol Renal Physiol. 2012;302:F1151–60.
Tamura Y, Tanabe K, Kitagawa W, Uchida S, Schreiner GF, Johnson RJ, et al. Nicorandil, a K(atp) channel opener, alleviates chronic renal injury by targeting podocytes and macrophages. Am J Physiol Renal Physiol. 2012;303:F339–49.
Sudo H, Hirata M, Kanada H, Yorozu K, Tashiro Y, Serizawa K, et al. Nicorandil improves glomerular injury in rats with mesangioproliferative glomerulonephritis via inhibition of proproliferative and profibrotic growth factors. J Pharmacol Sci. 2009;111:53–9.
Forbes MS, Thornhill BA, Park MH, Chevalier RL. Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury. Am J Pathol. 2007;170:87–99.
Katoh T, Takahashi K, Klahr S, Reyes AA, Badr KF. Dietary supplementation with l-arginine ameliorates glomerular hypertension in rats with subtotal nephrectomy. J Am Soc Nephrol. 1994;4:1690–4.
Zhou MS, Schuman IH, Jaimes EA, Raij L. Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-beta, and fibronectin with concomitant increase in nitric oxide bioavailability. Am J Physiol Renal Physiol. 2008;295:F53–9.
Serizawa K, Yogo K, Aizawa K, Tashiro Y, Takahari Y, Sekine K, et al. Paclitaxel-induced endothelial dysfunction in living rats is prevented by nicorandil via reduction of oxidative stress. J Pharmacol Sci. 2012;119:349–58.
Serizawa K, Yogo K, Aizawa K, Tashiro Y, Ishizuka N. Nicorandil prevents endothelial dysfunction due to antioxidative effects via normalisation of NADPH oxidase and nitric oxide synthase in streptozotocin diabetic rats. Cardiovasc Diabetol. 2011;10:105.
Tian N, Rose RA, Jordan S, Dwyer TM, Hughson MD, Manning RD Jr. N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension. J Hypertens. 2006;24:2263–70.
Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qiu P, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. 2005;68:2823–8.
Lee TM, Chang NC. Effect of nicorandil on proteinuria in well controlled hypertensive patients. J Hypertens. 2009;27:618–25.
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All authors are employees of Chugai Pharmaceutical Co., Ltd.
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Tashiro, Y., Yogo, K., Serizawa, K. et al. Nicorandil suppresses urinary protein excretion and activates eNOS in Dahl salt-sensitive hypertensive rats. Clin Exp Nephrol 19, 343–349 (2015). https://doi.org/10.1007/s10157-014-0998-6
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DOI: https://doi.org/10.1007/s10157-014-0998-6