Ischemic acute renal failure (ARF) is a frequent clinical syndrome with high morbidity and mortality.1) Reperfusion of previously ischemic renal tissue initiates a complex cellular events that results in injury and the eventual death of renal cells due to a combination of apoptosis and necrosis.2)The molecular mechanisms underlying the ischemia/reperfusion-induced renal injury are poorly understood, but it has been reported that several causal factors (ATP depletion, reactive oxygen species, phospholipase activation, neutrophil infiltration, vasoactive peptides etc.) are contributive to the pathogenesis of this renal damage.3) Enhancement of renal sympathetic nerve activity and its consequent effect on noradrenaline (NA) overflow from the nerve endings has also been considered as one of the factors which cause the ischemia/reperfusion-induced renal injury. 4,5) In a recent study, we found that ischemia/reperfusion-induced ARF was attenuated by a surgical or pharmacological blockade of renal sympathetic nerve, followed by a suppression of elevated renal venous NA levels. 6) 4-Hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) is a membrane-permeable and metal-independent superoxide dismutase mimetic that has been shown to be specific for superoxide anion (O 2 Ϫ ). 7,8) Several studies have demonstrated that tempol could reduce the renal dysfunction and injury caused by ischemia/reperfusion, mainly through its free radical scavenging activity.9,10) It is accumulating evidence that oxidative stress is one of causal factors in developing various cardiovascular diseases and that antioxidative agents and substances can attenuate cardiovascular diseases such as hypertension and post-ischaemic organ damage. 11,12) In addition, recent studies have shown that tempol-induced reduction in O 2 Ϫ production leads to decreased activity of renal sympathetic nerve, which may be contributive to the hypotensive action of tempol. 13,14) These findings led us to evaluate the relationship between tempol-induced improvement on the postischemic ARF and renal sympathetic nervous system.In the present study, we investigated the effect of tempol treatment on ischemia/reperfusion-induced renal dysfunction, tissue injury and NA levels in renal venous plasma, which are elevated in the post-ischemic kidney and involved in the post-ischaemic ARF. [4][5][6] In addition, we examined the effect of tempol on renal endothelin-1 (ET-1) overproduction, which is a possible mediator of the pathogenesis of the postischaemic ARF. [15][16][17]
MATERIALS AND METHODS
Animals and Experimental DesignMale SpragueDawley rats (10 weeks of age, Japan SLC, Shizuoka, Japan) were used. Animals were housed in a light-controlled room with a 12 h light/dark cycle and were allowed ad libitum access to food and water. Experimental protocols and animal care methods in the experiments were approved by the Experimental Animal Committee at Osaka University of Pharmaceutical Sciences. Two weeks before the study (at 8 weeks of age), the right kidney was removed through a smal...