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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Renoprotective Effects of l-Carnosine on Ischemia/Reperfusion-Induced Renal Injury in Rats

Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan (H.K., T.F., H.T., T.K., M.O., M.T., Y.M.); Institute for Health Care Science, Suntory Ltd., Osaka, Japan (N.T., Y.K.); Department of Pharmacology, Osaka University of Graduate School of Medicine, Osaka, Japan (Y.O.); and Research Equipment Center (Y.F.) and Department of Pharmacology (T.S., A.N., Y.A.), Kagawa University Medical School, Kagawa, Japan

We examined the renoprotective effects of l-carnosine (-alanyl-l-histidine) on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. In vehicle (0.9% saline)-treated rats, renal sympathetic nerve activity (RSNA) was significantly augmented during the renal ischemia, and renal function was markedly decreased at 24 h after reperfusion. Intracerebroventricular injection of l-carnosine (1.5 and 5 pmol/rat) to ischemic ARF rats dose-dependently suppressed the augmented RSNA during ischemia and the renal injury at 24 h after reperfusion. N--Acetyl-l-carnosine [N-acetyl--alanyl-l-histidine; 5 pmol/rat intracerebroventricular (i.c.v.)], which is resistant to enzymatic hydrolysis by carnosinase, did not affect the renal injury, and l-histidine (5 pmol/rat i.c.v.), a metabolite cleaved from l-carnosine by carnosinase, ameliorated the I/R-induced renal injury. Furthermore, a selective histamine H₃ receptor antagonist, thioperamide (30 nmol/rat i.c.v.) eliminated the preventing effects by l-carnosine (15 nmol/rat intravenously) on ischemic ARF. In contrast, a selective H₃ receptor agonist, R--methylhistamine (5 pmol/rat i.c.v.), prevented the I/R-induced renal injury as well as l-carnosine (5 pmol/rat) did. These results indicate that l-carnosine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppressing the enhanced RSNA during ischemia. In addition, the present findings suggest that the renoprotective effect of l-carnosine on ischemic ARF is induced by its conversion to l-histidine and l-histamine and is mediated through the activation of histamine H₃ receptors in the central nervous system.

Address correspondence to: Dr. Yasuo Matsumura, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. E-mail: matumrh{at}gly.oups.ac.jp

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