Renoprotective effects of l-carnosine on ischemia/reperfusion-induced renal injury in rats.
We examined the renoprotective effects of l-carnosine (beta-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-alpha-Acetyl-l-carnosine [N-acetyl-beta-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 H(3) 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 H(3) receptor agonist, R-alpha-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 H(3) receptors in the central nervous system.
Kurata
Hayato
H
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Fujii
Toshihide
T
Tsutsui
Hidenobu
H
Katayama
Tomoaki
T
Ohkita
Mamoru
M
Takaoka
Masanori
M
Tsuruoka
Nobuo
N
Kiso
Yoshinobu
Y
Ohno
Yukihiro
Y
Fujisawa
Yoshihide
Y
Shokoji
Takatoshi
T
Nishiyama
Akira
A
Abe
Youichi
Y
Matsumura
Yasuo
Y
D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002336:Carnosine / Q000378:metabolism / Q000627:therapeutic use*; D006639:Histidine / Q000627:therapeutic use; D007276:Injections, Intraventricular; D007668:Kidney / Q000098:blood supply* / Q000294:innervation; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D013564:Sympathetic Nervous System / Q000187:drug effects
D010880:Piperidines; D006639:Histidine; D002336:Carnosine; C052075:thioperamide