QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: jpet.104.074427v1 312/1/153    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamasowa, H. Articles by Matsumura, Y. Search for Related Content PubMed PubMed Citation Articles by Yamasowa, H. Articles by Matsumura, Y.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Endothelial Nitric Oxide Contributes to the Renal Protective Effects of Ischemic Preconditioning

Department of Pharmacology, Osaka University of Pharmaceutical Science, Nasahara, Takatsuki, Osaka, Japan

Received for publication July 16, 2004
Accepted August 12, 2004.

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
We determined whether endothelial nitric oxide synthase (eNOS) plays an important role in the renal protective effect of ischemic preconditioning (IP) against the ischemia/reperfusion-induced acute renal failure (ARF) by using eNOS-deficient (eNOS^-/-) and wild-type (eNOS^+/+) mice. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. IP, which consists of three cycles of 2-min ischemia followed by 5-min reperfusion, was performed prior to 45-min ischemia. In eNOS^+/+ mice, IP treatment markedly attenuated the ischemia/reperfusion-induced renal dysfunction and significantly improved histological renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Constitutive nitric oxide synthase activity in the kidney without IP was markedly decreased 6 h after reperfusion, but this decreased response was not observed in eNOS^+/+ mice with IP treatment. The improvement of renal dysfunction in eNOS^+/+ mice with IP treatment was abolished by pretreatment with N^G-nitro-L-arginine, a nonselective NOS inhibitor, whereas aminoguanidine, an inducible NOS inhibitor, had no effect. Finally, no protective effects of IP on ischemia/reperfusion-induced renal dysfunction and histological damage were observed in eNOS^-/- mice. These findings strongly support the view that eNOS-mediated NO production plays a pivotal role in the protective effect of IP on ischemia/reperfusion-induced ARF.

Endogenous NO is synthesized by the enzyme NO synthase (NOS), catalyzing the substrate, L-arginine, to L-citrulline and NO. Three different NOS isoforms have been cloned and characterized: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Both eNOS and nNOS are constitutively expressed NOS isoforms whose activity is regulated by the cytosolic concentration of calcium and by the presence of cofactors such as FAD/FMD, NADPH, and tetra-hydrobiopterin; therefore, eNOS and nNOS are known as constitutive NOS (cNOS) (Knowles and Moncada, 1994). On the other hand, iNOS is a calcium-independent synthase whose activity appears to rely on its protein expression induced by transcription factors such as nuclear factor-B (Knowles and Moncada, 1994). In the heart, it has been reported that iNOS and/or eNOS are involved in the cardioprotective effect of IP, both in early and delayed preconditioning (Bolli et al., 1997; Takano et al., 1998; Bell and Yellon, 2001; Bell et al., 2002; Shinmura et al., 2002). Although there is some information on the possible involvement of NO in renal IP (Torras et al., 2002), it remains obscure which type of NOS isoform is involved in the renal protective effect of IP. One available piece of evidence has been reported by Ogawa et al. (2001), who obtained findings that the renal protective effect of IP against the I/R-induced injury was abolished by N^G-nitro-L-arginine, a nonselective NOS inhibitor and was enhanced by L-arginine treatment. Furthermore, they found that IP alone does not lead to iNOS protein expression, whereas the I/R with or without IP treatment enhanced the protein expression, suggesting that NO production mediated by iNOS activity may contribute to the renal protective effect of IP. However, the above study was evaluated on the renal hemodynamic function in the acute phase of reperfusion injury (30–60 min after the reperfusion). Thus, the role of NO/NOS system in delayed preconditioning in the kidney remains to be elucidated.

Most recently, we have found that the protective effect of IP on I/R-induced acute renal failure (ARF), which is observed 24 h after reperfusion, is associated with renal NO production following the increase in eNOS protein expression after reperfusion (Yamashita et al., 2003). However, there is no direct evidence that eNOS is responsible for the renal protective effect of IP. To confirm this, we evaluated the effects of pharmacological blockade and the genetic deficiency of eNOS in IP-mediated renal protection from I/R-induced injury.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
Animals and Experimental Design. C57bl/6J wild-type and eNOS^-/- mice (20–25 g, 11–13 weeks old, The Jackson Laboratory, Bar Harbor, ME) 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, the right kidney was removed through a small flank incision under pentobarbital anesthesia (50 mg/kg i.p.). After a 2-week recovery period, these mice were separated into three groups: sham-operated control, I/R group (untreated ARF): 45-min ischemia followed by 24-h reperfusion, and IP treatment group (IP + ARF): three cycles of 2-min ischemia followed by 5-min reperfusion prior to I/R. The mice were anesthetized with pentobarbital (50 mg/kg i.p.), and the left kidney was exposed through a small flank incision. The left renal artery and vein were occluded with a non-traumatic clamp. At the end of the ischemic period, the clamp was released to allow reperfusion. In sham-operated control mice, the kidney was treated identically, except for clamping. Animals were housed in metabolic cages at 24 h after reperfusion; 24-h urine samples were taken, and blood samples were drawn from the thoracic aorta at the end of the urine collection period. The plasma was separated by centrifugation. These samples were used for measurements of renal function parameters. The kidneys were excised and examined using a light microscope.

In separate experiments, left kidneys were obtained just after IP treatment and at 0, 6, and 24 h after reperfusion, and NOS activities were measured. To evaluate the effects of the pharmacological blockade of NOS activities on IP-mediated renal protection, N^G-nitro-L-arginine (NO-ARG, 10 mg/kg i.v.), a nonselective NOS inhibitor, or aminoguanidine (10 mg/kg i.v.), an iNOS inhibitor, was pretreated 5 min before starting IP as a slow bolus injection (1 ml/kg) into the external jugular vein, and renal functional parameters were determined as described. The doses of these drugs were determined based on previous studies (Toda et al., 1993; Ortiz et al., 1996).

Histological Studies. The excised kidneys were preserved in phosphate-buffered 10% formalin, embedded in paraffin wax, and cut into thin sections (4 µm) according to conventional techniques. The sections were stained with hematoxylin and eosin. Histopathological changes were analyzed for tubular necrosis, proteinaceous casts, and medullary congestion, as suggested by Solez et al. (1974). Tubular necrosis and proteinaceous casts were graded as follows: no damage (0), mild (+1, unicellular, patchy isolated damage), moderate (+2, damage less than 25%), severe (+3, damage between 25 and 50%), and very severe (+4, more than 50% damage). The degree of medullary congestion was defined by: no congestion (0), mild (+1, vascular congestion with identification of erythrocytes by 400x magnification), moderate (+2, vascular congestion with identification of erythrocytes by 200x magnification), severe (+3, vascular congestion with identification of erythrocytes by 100x magnification), and very severe (+4, vascular congestion with identification of erythrocytes by 40x magnification). Evaluations were made in a blind manner.

Renal Functional Parameters. Blood urea nitrogen (BUN) and creatinine levels in plasma (Pcr) were determined using a commercial assay kit, BUN-test-Wako and Creatinine-test-Wako (Wako Pure Chemicals, Osaka, Japan), respectively. Urinary osmolality (Uosm) was measured by freezing-point depression (Fiske Associates, Uxbridge, MA).

Measurement of NOS Activity. Ca²⁺-dependent and -independent NOS activities (cNOS and iNOS activities, respectively) were determined by measuring the conversion of L-[³H]arginine to L-[³H] citrulline using a NOS detection kit (NOS detection kit BOX-2; Sigma-Aldrich, St. Louis, MO). Briefly, whole frozen kidneys were homogenized in ice-cold homogenization buffer containing protease inhibitors. Homogenates were centrifuged (30 min at 5000g) to remove tissue debris, and the supernatant was utilized for the measurement of NOS activities. The samples were incubated in assay buffer containing 0.323 µM L-[³H]arginine, 600 µM CaCl₂, and 1 mM NADPH, in the presence of an excess amount of calmodulin, at 37°C for 30 min. After stopping the reaction, the samples were centrifuged (3 min at 3000 rpm), and radioactive activities of L-[³H]citrulline were measured using a liquid scintillation counter (TRI-CARB; Packard, Tokyo, Japan). To determine Ca²⁺-independent NOS (iNOS) activity, the assay was conducted in the presence of 10 mM EDTA without CaCl₂. Ca²⁺-dependent NOS (cNOS) activity was calculated by subtracting iNOS activity from total NOS activity.

Drugs. NO-ARG (Peptide Institute Inc., Osaka, Japan) and aminoguanidine (Tocris Cookson Inc., Bristol, UK) were dissolved in 0.9% saline.

Statistical Analysis. Values are expressed as the mean ± S.D. Relevant data were processed by InStat (GraphPad Software for Science; GraphPad Software Inc., San Diego, CA). For statistical analysis, we used the unpaired Student's t test for two-group comparison and one-way analysis of variance followed by Dunnett's tests for multiple comparisons. Histological data were analyzed using the Mann-Whitney test. For all comparisons, differences were considered significant at P < 0.05.

	Results

Top Abstract Materials and Methods Results Discussion References

 
Effects of IP Treatment on I/R-Induced Renal Dysfunction. As shown in Fig. 1, the renal functional parameters of mice subjected to 45-min ischemia showed marked deterioration, as measured 24 to 48 h after reperfusion. As compared with sham-operated control mice, I/R (untreated ARF) mice exhibited significant increases in BUN, Pcr, and urine flow (UF) and significant decreases in Uosm. However, I/R-induced changes in renal functional parameters were markedly attenuated by IP treatment (IP + ARF).

View larger version (24K): [in this window] [in a new window]   Fig. 1. Effects of I/R with or without IP treatment on BUN (A), Pcr (B), UF (C), and Uosm (D). At 24 h after reperfusion, 24-h urine was collected. Each value represents the mean ± S.D. *, P < 0.01, compared with I/R mice without IP treatment (untreated ARF).

Effects of IP Treatment on I/R-Induced Histological Renal Damage. Histological examination revealed severe lesions in the kidney of untreated ARF mice (48 h after the 45-min ischemia and reperfusion). These changes were characterized by tubular necrosis (outer zone outer stripe of medulla), proteinaceous casts in tubuli (inner zone of medulla), and medullary congestion and hemorrhage (outer zone inner stripe of medulla). IP treatment markedly improved the development of all these lesions (Table 1). Typical photographs are shown in Fig. 2.

View larger version (134K): [in this window] [in a new window]   Fig. 2. Light microscopy of the inner zone (A–C), outer zone inner stripe (D–F), and outer zone outer stripe (G–I) of the kidney of sham-operated control and I/R mice with or without (untreated ARF) IP treatment. Arrows indicate proteinaceous casts in tubuli (B), congestion and hemorrhage (E), and tubular necrosis (H).

Measurement of NOS Activity in the Kidney. Changes of NOS activity were evaluated in kidneys exposed to I/R with or without IP treatment. As shown in Fig. 3A, IP treatment alone and 45-min ischemia with or without IP treatment exhibited no changes in cNOS activity compared with sham-operated mice. cNOS activity was significantly reduced at 6 h after reperfusion in I/R mice without IP, but the reduced level recovered at 24 h after reperfusion. On the other hand, the I/R-induced reduction of cNOS activity at 6 h after reperfusion was not observed in the kidney with IP treatment. As shown in Fig. 3B, iNOS activities were not detected in kidneys of the sham-operated control, IP treatment alone and 45-min ischemia with or without IP treatment. However, at 6 and 24 h after reperfusion, there were notable increases in iNOS activities, which were markedly suppressed by the IP treatment.

View larger version (22K): [in this window] [in a new window]   Fig. 3. Renal cNOS (A) and iNOS (B) activities in a sham-operated control, IP alone, and I/R mice with or without (untreated ARF) IP treatment. Each value represents the mean ± S.D. *, P < 0.01, compared with sham-operated mice. , P < 0.01, compared with I/R mice without IP pretreatment (untreated ARF). N.D., not detected.

Effects of NOS Inhibitors on Renal Protection by IP Treatment. We next examined the effects of the pharmacological blockade of NOS activities on IP-mediated renal protection. As shown in Fig. 4, the pretreatment with NO-ARG, a nonselective NOS inhibitor, almost completely abolished the renal protective effects of IP against I/R-induced renal dysfunction. On the other hand, aminoguanidine, a preferential inhibitor of iNOS, had no effect on the IP-induced improvement of renal dysfunction.

View larger version (29K): [in this window] [in a new window]   Fig. 4. Effects of NO-ARG or aminoguanidine on BUN (A), Pcr (B), UF (C), and Uosm (D) of I/R mice with IP treatment (IP + ARF). At 24 h after reperfusion, 24-h urine was collected. Each value represents the mean ± S.D. *, P < 0.05; **, P < 0.01, compared with IP + ARF.

I/R-Induced Renal Dysfunction and Effects of IP Treatment in eNOS^-/- Mice. As shown in Fig. 5, there was marked impairment of renal function in eNOS^-/- mice subjected to 45-min ischemia, as measured 24 to 48 h after reperfusion, showing a tendency to further deterioration compared with wild-type mice. In contrast to the case in wild-type animals (Fig. 1), IP treatment failed to improve I/R-induced renal dysfunction. In addition, some mice exposed to 45-min ischemia and reperfusion died between 24 to 48 h (two of eight mice in both groups, respectively).

View larger version (21K): [in this window] [in a new window]   Fig. 5. Effects of I/R with or without IP treatment on BUN (A), Pcr (B), UF (C), and Uosm (D) in eNOS-/- mice. At 24 h after reperfusion, 24-h urine was collected. Each value represents the mean ± S.D. *, P < 0.01, compared with eNOS-/- I/R mice without IP treatment (untreated ARF).

I/R-Induced Histological Renal Damage and Effects of IP Treatment in eNOS^-/- Mice. Histological examination revealed severe lesions in the kidney of untreated eNOS^-/- mice (48 h after 45-min ischemia and reperfusion), as seen in wild-type animals. However, in contrast to the findings observed in wild-type animals, IP treatment of eNOS^-/- mice did not attenuate I/R-induced histological damage (Fig. 6; Table 2).

View larger version (142K): [in this window] [in a new window]   Fig. 6. Light microscopy of the inner zone (A–C), outer zone inner stripe (D–F), and outer zone outer stripe (G–I) of the kidney of eNOS-/- sham-operated control and I/R mice with or without (untreated ARF) IP treatment. Arrows indicate proteinaceous casts in tubuli (B and C), congestion and hemorrhage (E and F), and tubular necrosis (H and I).

	Discussion

Top Abstract Materials and Methods Results Discussion References

 
Our recent study using rats demonstrated that the protective effect of IP on I/R-induced renal dysfunction and tissue injury correlated with eNOS protein expression and NO production in the kidney (Yamashita et al., 2003). This study was performed to determine whether the eNOS/NO system is responsible for IP-mediated renal protection. We obtained evidence that an IP-mediated improvement on postischemic renal injury at 24 to 48 h after reperfusion was observed in wild-type mice, but not in eNOS^-/- mice, in which there was somewhat augmented renal dysfunction in the postischemic kidney. Pretreatment with NO-ARG, a nonselective NOS inhibitor, abolished the protective effect of IP, whereas aminoguanidine, an iNOS inhibitor, failed to affect the IP-mediated renal protection. Thus, it seems likely that the eNOS/NO system plays a crucial role in the IP effect on I/R-induced renal injury.

Lieberthal et al. (1991) found that impairment of renal hemodynamics in rats with hypovolemic shock induced by hemorrhage was to some extent overcome by the inhibition of NO production. The NO synthase inhibitor was reported to prevent hypoxia/reoxygenation injury in rat proximal tubules, thereby suggesting that NO is synthesized in proximal tubules and is involved in tubular hypoxia/reoxygenation injury (Yu et al., 1994). In contrast, Chintala et al. (1993) noted that the inhibition of NO production with an NO synthase inhibitor significantly deteriorated the renal function of the postischemic kidney in anesthetized rats, whereas pretreatment with the NO precursor L-arginine abolished the NO synthase inhibitor-induced deterioration of renal function. Similar improvement by L-arginine against the decreased renal function in ischemic ARF was noted by Schramm et al. (1994), although they observed no detrimental effect of the NO synthase inhibitor. We found that I/R-induced renal dysfunction and tissue injury were markedly attenuated by preischemic treatment with FK-409, a spontaneous NO releaser (Matsumura et al., 1998). Thus, the pathophysiological roles of NO in ischemic ARF are controversial. Recent studies clearly demonstrated that renal I/R injury was efficiently attenuated by genetic deficiency or the pharmacological blockade of iNOS (Ling et al., 1999; Walker et al., 2000; Chatterjee et al., 2002), hypothesizing that iNOS-generated NO mediates I/R-induced renal damage. One possibility is that a toxic peroxynitrite, a reactive substance of NO with superoxide anion, may cause renal damage via direct oxidant injury and protein tyrosine nitration (Walker et al., 2000; Chatterjee et al., 2002). Although iNOS-derived NO predominantly elicits pathologic effects, eNOS-derived NO is believed to be responsible for maintaining physiologic renal hemodynamics and functions (Goligorsky and Noiri, 1999). Thus, the heterogeneity of the effects of NO in the pathophysiology of renal I/R injury seems to be closely related to the alterations of iNOS and eNOS (or cNOS) expression and/or activity.

In this study, cNOS activity in the kidney was decreased 6 h after reperfusion, whereas iNOS activity, which was not detected before and immediately after ischemia, gradually increased after reperfusion. IP treatment completely restored the decreased cNOS activity to the basal level and suppressed the elevation of iNOS activity. Thus, the I/R injury seems to be associated with the imbalance of cNOS and iNOS activities, and the improvement of this imbalance may be involved in the IP-mediated renal protective effects.

The precise mechanisms by which IP treatment prevents the loss of cNOS activity after reperfusion are unclear. Changes in eNOS protein expression seem to be at least partly related to those of cNOS activities. Most recently, Muscari et al. (2004) demonstrated that cardiac IP inhibits the loss of eNOS protein expression and enhances its activity in rat hearts exposed to I/R. We also observed that eNOS protein expression was increased in the postischemic rat kidney with IP treatment (Yamashita et al., 2003). Further studies are required to clarify the mechanisms underlying the IP-induced increase in eNOS protein expression.

The signaling mechanisms underlying the NO-mediated IP effect have been discussed. In isolated rat hearts, Lochner et al. (2000) indicated the importance of the NO-guanylyl cyclase-cyclic GMP pathway in the cardioprotective effects of IP by using NO donors and inhibitors of NOS and guanylyl cyclase. It has been demonstrated that the activation and translocation of PKC during cardiac IP is NO dependent (Ping et al., 1999). The mitochondrial K⁺_ATP channel, which is contributive to IP-mediated myocardial protection (Auchampach and Gross, 1993), could be activated by an NO donor in ventricular myocytes (Sasaki et al., 2000). In addition, it has been reported that hepatic IP is mediated by the inhibitory action of NO in endothelin-1 overproduction induced by I/R (Peralta et al., 1996). There is growing evidence that endothelin-1 is closely related to the development of I/R-induced ARF (Takaoka et al., 2000). In a recent study, we obtained evidence that renal endothelin-1 overproduction induced by I/R was markedly suppressed by IP treatment (Yamashita et al., 2003). Taken together with the view that exogenous and endogenous NO could suppress endothelial endothelin-1 production (Mitsutomi et al., 1999), the down-regulation of endothelin-1 biosynthesis may be involved at least partly in NO-mediated renal protection by IP.

We propose that eNOS-mediated NO production plays a crucial role in delayed preconditioning of the mouse kidney. Moreover, the attenuation of iNOS activity and/or the improvement of cNOS/iNOS imbalance may be involved in the IP-mediated renal protective effects.

	Acknowledgements

 
We thank Daniel Mrozek for reading the manuscript.

	Footnotes

 
This work was supported by a Grant-in-Aid for High Technology Research and a Grant-in-Aid for Scientific Research 14570092 (to Y.M.) from the Ministry of Education, Science, Sports, and Culture of Japan.

doi:10.1124/jpet.104.074427.

ABBREVIATIONS: I/R, ischemia/reperfusion; IP, ischemic preconditioning; PKC, protein kinase C; K⁺_ATP channel, ATP-sensitive potassium channel; NO, nitric oxide; NOS, NO synthase; nNOS, neuronal NOS; eNOS, endothelial NOS; iNOS, inducible NOS; cNOS, constitutive NOS; ARF, acute renal failure; NO-ARG, N^G-nitro-L-arginine; BUN, blood urea nitrogen; Pcr, plasma creatinine concentration; Uosm, urinary osmolality; UF, urine flow.

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

	References

Top Abstract Materials and Methods Results Discussion References

 

Auchampach JA and Gross GJ (1993) Adenosine A₁ receptor, K_ATP channels and ischemic preconditioning in dogs. Am J Physiol 264: H1321–H1336.
Bell RM, Smith CC, and Yellon DM (2002) Nitric oxide as a mediator of delayed pharmacological (A(1) receptor triggered) preconditioning: is eNOS masquerading as iNOS? Cardiovasc Res 53: 405–413.[Abstract/Free Full Text]
Bell RM and Yellon DM (2001) The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: the lowering of the preconditioning threshold: an investigation in eNOS knockout mice. Cardiovasc Res 52: 274–280.[Abstract/Free Full Text]
Bolli R (2000) The late phase of preconditioning. Circ Res 87: 972–983.[Abstract/Free Full Text]
Bolli R, Bhatti ZA, Tang XL, Qiu Y, Zhang Q, Guo Y, and Jadoon AK (1997) Evidence that late preconditioning against myocardial stunning in conscious rabbits is triggered by the generation of nitric oxide. Circ Res 81: 42–52.[Abstract/Free Full Text]
Chatterjee PK, Patel NS, Kvale EO, Cuzzocrea S, Brown PA, Stewart KN, Mota-Filipe H, and Thiemermann C (2002) Inhibition of inducible nitric oxide synthase reduces renal ischemia/reperfusion injury. Kidney Int 61: 862–871.[CrossRef][Medline]
Chintala MS, Chiu PJS, Vemulapalli S, Watkins RW, and Sybertz EJ (1993) Inhibition of endothelial derived relaxing factor (EDRF) aggravates ischemic acute renal failure in anesthetized rats. Naunyn-Schmiedeberg's Arch Pharmacol 348: 305–310.[Medline]
Downey JM, Liu GS, and Thornton JD (1993) Adenosine and the anti-infarct effects of preconditioning. Cardiovasc Res 27: 3–8.[Free Full Text]
Goligorsky MS and Noiri E (1999) Duality of nitric oxide in acute renal injury. Semin Nephrol 19: 263–271.[Medline]
Gross GJ and Fryer RM (1999) Sarcolemma versus mitochondrial ATP-sensitive K⁺ channels and myocardial preconditioning. Circ Res 84: 973–979.[Abstract/Free Full Text]
Heurteaux C, Lauritzen I, Widmann C, and Lazdunski M (1995) Essential role of adenosine, adenosine A₁ receptors and ATP-sensitive K⁺ channels in cerebral ischemic preconditioning. Proc Natl Acad Sci USA 92: 4666–4670.[Abstract/Free Full Text]
Knowles RG and Moncada S (1994) Nitric oxide synthase in mammals. Biochem J 298: 249–258.
Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, and Tada M (1993) Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72: 1293–1299.[Abstract/Free Full Text]
Lee HT and Emala CW (2000) Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A₁ and A₃ receptors. Am J Physiol 278: F380–F387.
Lieberthal W, McGarry AE, Sheils J, and Valeri CR (1991) Nitric oxide inhibition in rats improves blood pressure and renal function during hypovolemic shock. Am J Physiol 261: F868–F872.
Ling H, Edelstein C, Gengaro P, Meng X, Lucia S, Knotek M, Wangsiripaisan A, Shi Y, and Schrier R (1999) Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. Am J Physiol 277: F383–F390.
Lochner A, Marais E, Genade S, and Moolman JA (2000) Nitric oxide: a trigger for classic preconditioning? Am J Physiol 279: H2752–H2765.
Matsumura Y, Nishiura M, Deguchi S, Hashimoto N, Ogawa T, and Seo R (1998) Protective effect of FK409, a spontaneous nitric oxide releaser, on ischemic acute renal failure in rats. J Pharmacol Exp Ther 287: 1084–1091.[Abstract/Free Full Text]
Mitsutomi N, Akashi C, Odagiri J, and Matsumura Y (1999) Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. Eur J Pharmacol 364: 65–73.[CrossRef][Medline]
Miura T, Liu Y, Kita H, Ogawa T, and Shimamoto K (2000) Roles of mitochondrial ATP-sensitive K⁺ channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation. J Am Coll Cardiol 35: 238–245.[Abstract/Free Full Text]
Murry CE, Jennings RB, and Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cellular injury in ischemic myocardium. Circulation 74: 1124–1136.[Abstract/Free Full Text]
Muscari C, Bonafe' F, Gamberini C, Giordano E, Tantini B, Fattori M, Guarnieri C, and Caldarera CM (2004) Early preconditioning prevents the loss of endothelial nitric oxide synthase and enhances its activity in the ischemic/reperfused rat heart. Life Sci 74: 1127–1137.[CrossRef][Medline]
Ogawa T, Nussler AK, Tuzuner E, Neuhaus P, Kaminishi M, Mimura Y, and Beger HG (2001) Contribution of nitric oxide to the protective effects if ischemic preconditioning in ischemia-reperfused rat kidney. J Lab Clin Med 138: 50–58.[CrossRef][Medline]
Ortiz MC, Fortepiani LA, Martinez C, Atucha NM, and Garcia-Estan J (1996) Renal and pressor effects of aminoguanidine in cirrhotic rats with ascites. J Am Soc Nephrol 7: 2694–2699.[Abstract]
Peralta C, Closa D, Hotter G, Gelpi E, Prats N, and Rosello-Catafau J (1996) Liver ischemic preconditioning is mediated by the inhibitory action of nitric oxide on endothelin. Biochem Biophys Res Commun 229: 264–270.[CrossRef][Medline]
Peralta C, Hotter G, Closa D, Prats N, Xaus C, Gelpi E, and Rosello-Catafau J (1999) The protective role of adenosine in inducing nitric oxide synthesis in rat liver ischemia preconditioning is mediated by activation of A₂ receptors. Hepatology 29: 126–132.[CrossRef][Medline]
Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, Banerjee S, Dawn B, Balafonova Z, and Bolli R (1999) Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res 84: 587–604.[Abstract/Free Full Text]
Sasaki N, Sato T, Ohler A, O'Rourke B, and Marban E (2000) Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 101: 439–445.[Abstract/Free Full Text]
Schramm L, Heidbreder E, Schmitt A, Kartenbender K, Zimmermann J, Ling H, and Heidland A (1994) Role of L-arginine-derived NO in ischemic acute renal failure in the rat. Renal Failure 16: 555–569.[Medline]
Schroeder CA Jr, Lee HT, Shah PM, Babu SC, Thompson CI, and Belloni FL (1996) Preconditioning with ischemia or adenosine protects skeletal muscle from ischemic tissue reperfusion injury. J Surg Res 63: 29–34.[CrossRef][Medline]
Shinmura K, Xuan YT, Tang XL, Kodani E, Han H, Zhu Y, and Bolli R (2002) Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res 90: 602–608.[Abstract/Free Full Text]
Solez K, Kramer EC, Fox JA, and Heptinstall RH (1974) Medullary plasma flow and intravascular leukocyte accumulation in acute renal failure. Kidney Int 6: 24–37.[Medline]
Takano H, Manchikalapudi S, Tang XL, Qiu Y, Rizvi A, Jadoon AK, Zhang Q, and Bolli R (1998) Nitric oxide synthase is the mediator of late preconditioning against myocardial infarction in conscious rabbits. Circulation 98: 441–449.[Abstract/Free Full Text]
Takaoka M, Kuro T, and Matsumura Y (2000) Role of endothelin in the pathogenesis of acute renal failure. Drug News Perspect 13: 141–146.[CrossRef][Medline]
Toda N, Kitamura Y, and Okamura T (1993) Neural mechanism of hypertension by nitric oxide synthase inhibitor in dogs. Hypertension 21: 3–8.[Abstract/Free Full Text]
Torras J, Herrero-Fresneda I, Lloberas N, Riera M, Cruzado JM, and Grinyó M (2002) Promising effects of ischemic preconditioning in renal transplantation. Kidney Int 61: 2218–2227.[CrossRef][Medline]
Walker LM, Walker PD, Imam SZ, Ali SF, and Mayeux PR (2000) Evidence for peroxynitrite formation in renal ischemia-reperfusion injury: studies with the inducible nitric oxide synthase inhibitor L-N(6)-(1-Iminoethyl)lysine. J Pharmacol Exp Ther 295: 417–422.[Abstract/Free Full Text]
Yamashita J, Ogata M, Itoh M, Yamasowa H, Shimeda Y, Takaoka M, and Matsumura Y (2003) Role of nitric oxide in the renal protective effects of ischemic preconditioning. J Cardiovasc Pharmacol 42: 419–427.[CrossRef][Medline]
Yellon DM and Baxter GF (1995) A "second window of protection" or delayed preconditioning phenomenon: future horizons for myocardial protection? J Mol Cell Cardiol 27: 1023–1034.[CrossRef][Medline]
Yu L, Gengaro PE, Niederberger M, Burke TJ, and Schrier RW (1994) Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury. Proc Natl Acad Sci USA 91: 1691–1695.[Abstract/Free Full Text]

This article has been cited by other articles:

				V. Ramirez, J. Trujillo, R. Valdes, N. Uribe, C. Cruz, G. Gamba, and N. A. Bobadilla Adrenalectomy prevents renal ischemia-reperfusion injury Am J Physiol Renal Physiol, October 1, 2009; 297(4): F932 - F942. [Abstract] [Full Text] [PDF]

				D. E. Choi, J. Y. Jeong, B. J. Lim, S. Chung, Y. K. Chang, S. J. Lee, K. R. Na, S. Y. Kim, Y. T. Shin, and K. W. Lee Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats Am J Physiol Renal Physiol, August 1, 2009; 297(2): F362 - F370. [Abstract] [Full Text] [PDF]

				O. Toprak, M. Cirit, M. Tanrisev, C. Yazici, O. Canoz, M. Sipahioglu, A. Uzum, R. Ersoy, and E. Y. Sozmen Preventive effect of nebivolol on contrast-induced nephropathy in rats Nephrol. Dial. Transplant., March 1, 2008; 23(3): 853 - 859. [Abstract] [Full Text] [PDF]

				J. M. Mejia-Vilet, V. Ramirez, C. Cruz, N. Uribe, G. Gamba, and N. A. Bobadilla Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone Am J Physiol Renal Physiol, July 1, 2007; 293(1): F78 - F86. [Abstract] [Full Text] [PDF]

				A. Grenz, T. Eckle, H. Zhang, D. Y. Huang, M. Wehrmann, C. Kohle, K. Unertl, H. Osswald, and H. K. Eltzschig Use of a hanging-weight system for isolated renal artery occlusion during ischemic preconditioning in mice Am J Physiol Renal Physiol, January 1, 2007; 292(1): F475 - F485. [Abstract] [Full Text] [PDF]

				A. M. G. Versteilen, I. J. M. Korstjens, R. J. P. Musters, A. B. J. Groeneveld, and P. Sipkema Rho kinase regulates renal blood flow by modulating eNOS activity in ischemia-reperfusion of the rat kidney Am J Physiol Renal Physiol, September 1, 2006; 291(3): F606 - F611. [Abstract] [Full Text] [PDF]

				M. J. Burne-Taney, M. Liu, W. M. Baldwin, L. Racusen, and H. Rabb Decreased Capacity of Immune Cells to Cause Tissue Injury Mediates Kidney Ischemic Preconditioning. J. Immunol., June 1, 2006; 176(11): 7015 - 7020. [Abstract] [Full Text] [PDF]

				A. Nakajima, K. Ueda, M. Takaoka, Y. Yoshimi, and Y. Matsumura Opposite Effects of Pre- and Postischemic Treatments with Nitric Oxide Donor on Ischemia/Reperfusion-Induced Renal Injury J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1038 - 1046. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: jpet.104.074427v1 312/1/153    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamasowa, H. Articles by Matsumura, Y. Search for Related Content PubMed PubMed Citation Articles by Yamasowa, H. Articles by Matsumura, Y.