In vivo effects of monoclonal antibodies against rat beta(2) integrins on kidney ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (IR) involves adhesion of leukocytes to the activated endothelium, leading to tissue damage. CD11/CD18 beta(2) integrins interact with their ligands on endothelial cells and may therefore represent a therapeutic target for the prevention of IR. We investigated the effects of three monoclonal antibodies (mAbs) that recognize epitopes of heavy or light chain of the beta(2) integrins on IR in kidneys. METHODS: Uninephrectomized Fischer rats were subjected to 45 or 60 min of renal ischemia, treated with intravenously anti-beta(2) integrin monoclonal antibodies (anti-CD11a, anti-CD11b, and anti-CD18) 5 min prior to reperfusion, and compared to a nontreated group. Serum creatinine, blood urea nitrogen (BUN), and kidney histopathological damages were assessed at 1, 2, and 7 days after ischemia. RESULTS: After 45 and 60 min of ischemia, serum creatinine and BUN were significantly higher in the control than in animals treated with anti-CD11a and anti-CD18 at 24 and 48 h. Administration of anti-CD11b had a beneficial effect on renal function after 45 min but not after 60 min of ischemia. Histologic and immunostaining studies demonstrated mild tubular necrosis and less leukocyte infiltration in the anti-CD11a- and anti-CD18-treated groups compared to the control group. CONCLUSION: These results indicate that selected antibodies to CD11a/CD18 may decrease kidney IR injury when administered prior to reperfusion.     

Mesna: a novel renoprotective antioxidant in ischaemic acute renal failure.

BACKGROUND: Reactive oxygen species (ROS) play a key role in renal ischaemia-reperfusion injury. After establishing the in vitro anti-oxidative potential of mesna, a sulfhydryl-containing compound, its effect on kidney function and morphology in a rat model of ischaemic acute renal failure (ARF) was examined. METHODS: Mesna (180 mg/kg) was administered at different time points relative to ischaemia and/or reperfusion onset. Kidney function was assessed by glomerular filtration rate (GFR) and fractional sodium excretion (FE(Na)) before a 45-min period of unilateral renal artery clamping and following 90 min of reperfusion. Mesna was administered by bolus, 30 min before the induction of ischaemia, 5 min before ischaemia, 5 min before reperfusion, and 5 min after the onset of reperfusion. RESULTS: Mesna improved function of the ischaemic kidney at each administration. When mesna was administered 5 min before the onset of reperfusion, GFR reached 90-100% of its pre ischaemic value and FE(Na) was improved by 75%. The beneficial effect of mesna was also demonstrated by light and electron microscopy. Kidneys treated with mesna 5 min before reperfusion resembled ischaemic non-reperfused kidneys and showed subtle morphological and ultrastructural changes compared with ischaemic-reperfused kidneys. Mesna had no haemodynamic effect on renal blood flow and did not induce any osmotic diuresis. CONCLUSIONS: We suggest that mesna acts as an antioxidant. Its antioxidant potential together with optimal protection achieved when administered 5 min before reperfusion, supports the conclusion that mesna scavenges ROS generated at the onset of reperfusion, thus diminishing reperfusion injury and organ damage.     

阻断CD18介导的白细胞粘附对岛状皮瓣成活的影响

研究白细胞白细胞粘附在缺血再灌注损伤中的作用。方法，应用大鼠腹部岛状皮瓣模型，检测了皮瓣过氧化酶和丙二醛含量，观察了皮瓣的成活情况。结论ＣＤ１８介导 白细胞粘附参与了皮瓣再灌注损伤过程，抗ＣＤ１８单抗阻断白细胞附能减轻白细胞介导的组织损伤，并对岛状皮瓣具有保护作用。     

Role of PI3-kinase/Akt signalling pathway in renal function and cell proliferation after renal ischaemia/reperfusion injury in mice

BACKGROUND: PI3K/Akt pathway has been shown to play a critical role in the regulation of mitogenic signalling, apoptosis, cell proliferation and survival in a variety of cells and tissues. The aim of the present study was to investigate the role of PI3K/Akt pathway in the renal ischaemia/reperfusion. METHODS: Four experimental groups, sham-operative mice, vehicle-delivered and wortmannin-treated ischaemic/reperfusion injury mice, wortmannin-treated normal mice were designed to examined serum blood urea nitrogen level, renal injury, proliferating cell nuclear antigen protein and Akt phosphorylation status at 30 min, 90 min, 24 h, 48 h of reperfusion after ischaemic treatment. Wortmannin or its vehicle was given intraperitoneally at 4 h before surgery. Blood urea nitrogen was measured, and immunohistochemistry and western blotting were used to detect the components of PI3K/Akt pathway in the ischaemic/reperfusion injury kidney. RESULTS: PI3-kinase inhibitor wortmannin imposes a deleterious effect on serum blood urea nitrogen level, renal function after renal ischaemia/reperfusion injury in mice. The renal cell proliferation increased after ischaemia/reperfusion injury in mouse, which could be inhibited by wortmannin. Phosphorylation of Akt was increased after ischaemia/reperfusion in the mouse kidney, and reduced by wortmannin administration. CONCLUSION: This primary study suggests that PI3-kinase/Akt signalling pathway play an important role in the regulation of the renal repair after ischaemia/reperfusion injury.     

Relative roles of endothelin-1 and angiotensin II in experimental post-ischaemic acute renal failure.

BACKGROUND: The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF. METHODS: Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF. RESULTS: Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only approximately 35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure. CONCLUSIONS: These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF.     

ISCHAEMIC PRECONDITIONING OF THE LIVER: A PRELIMINARY STUDY

Background: A phenomenon of ‘preconditioning’ exists for the heart, but has not been described for the liver. This study was undertaken to determine whether a brief episode of ischaemia (3 or 5 min) followed by a short reperfusion time (5 or 10 min) would precondition the liver to reduce subsequent injury from prolonged ischaemia (30 to 90 min). Methods: Male Wistar rats were allocated into five control (no preconditioning) and five preconditioned groups, each having a liver resection. The preconditioning times were 3 rnin ischaemia followed by 5 rnin reperfusion with a prolonged ischaemia of 60 or 90 min for the first two groups, and 5 min ischaemia followed by 10 rnin reperfusion with prolonged ischaemia times of 30 or 45 min for the other three groups. Results: Of rats resected with 3–5–60 rnin time sequence designed to assess survival, 9/10 died. However 9/10 died also in the matching control group with 60 rnin ischaemia. With a 5–10–45 rnin sequence, 9/10 survived more than 24 h in the preconditioned group and 1/10 in the non-preconditioned controls. With a 5–10–30+ sequence designed to measure liver function tests, the prothrombin time was significantly improved; bilirubin, serum alkaline phosphatase and the alanine aminotransferase improved but these did not reach significance. Conclusion: A brief episode of ischaemia followed by an episode of reperfusion before a prolonged period of ischaemia ameliorated the effects of ischaemia-reperfusion injury in a rat liver resection model. If hepatic preconditioning is confirmed in humans, ischaemic preconditioning will have an important role for all liver surgery.     

Amelioration of post-ischaemic renal injury by contralateral uninephrectomy: a role of endothelin-1.

BACKGROUND: Previous studies showed that unilateral renal damage is attenuated by prior contralateral uninephrectomy (Nx) in ischaemia-induced acute renal failure (ARF). Since renal ischaemia increases endothelin-1 (ET-1) production in the kidney, we examined whether the alteration of renal ET-1 content may contribute to the nephrectomy-induced attenuation of renal injury. METHODS: Ischaemic renal injury was provoked by 60-min left renal artery occlusion (RAO). Removal of the right kidney was performed just before RAO in the Nx group. Forty-eight hours after release of the clamp, renal ET-1 content was measured in both non-nephrectomized and unilaterally nephrectomized rats. We also examined the effects of a selective ET(A) receptor (FR139317) and monoclonal ET antibody (AwETN40) on the RAO-induced changes in renal haemodynamics at 2 and 48 h after RAO respectively. RESULTS: The plasma concentration of ET-1 did not change in the two groups of ARF rats, but the cortical content of ET-1 increased to a lesser extent in Nx animals after ischaemia. Prior removal of the right kidney significantly facilitated the percentage recovery of left renal blood flow (RBF) during the first 2 h after release of the clamp. The percentage recovery of inulin clearance (Cin) by the kidney was also significantly better in Nx than sham-Nx rats at 48 h after RAO. Continuous administration of FR139317 (50 mg/kg/day) using osmotic minipumps for 3 days significantly attenuated exogenous ET-1-induced decrease in Cin and RBF. Infusion of FR139317 restored the decrease in RBF to control values during first 2 h in sham-Nx rats. However, FR139317 and AwETN40 did not ameliorate the RAO-induced decline of Cin in sham-Nx or Nx rats at 2 and 48 h after ischaemia respectively. CONCLUSIONS: Contralateral uninephrectomy prior to ischaemia-induced ARF attenuated the increase in cortical ET-1 content and subsequent renal response to ischaemic injury. This beneficial effect of unilateral nephrectomy, however, was not mediated through well-preserved RBF due to reduced intrarenal ET-1 action.     

Bosentan and losartan ameliorate acute renal failure associated with mild but not strong NO blockade.

BACKGROUND: Acute renal failure (ARF) is a devastating illness, especially when it occurs in various conditions with impaired nitric oxide (NO) synthesis, such as arterial hypertension, heart failure and some renal diseases. We have directed our investigations to effects of both angiotensin II (AII) and endothelin (ET) receptor blockade associated with mild or strong NO deficiency on haemodynamic, biochemical and morphological parameters in experimental post-ischaemic ARF. METHODS: In this study, we used bosentan (dual, ETA/ETB-receptor antagonist), losartan (non-peptide, competitive antagonist of type I AII receptor), and NG-nitro-L-arginine methyl ester (L-NAME), inhibitor of NO synthesis. Experiments were performed in anaesthetized, adult male Wistar rats. The right kidney was removed and the renal ischaemia was performed by clamping the left renal artery for 45 min. Experimental groups received receptor antagonists (bosentan or losartan) or vehicle (saline) in the femoral vein 20 min before, during and 20 min after the period of ischaemia. L-NAME was given as i.v. bolus before each antagonist infusion. All parameters were measured 24 h after reperfusion. RESULTS: Our results showed that strong NO blockade overcame effects of both ET and AII receptor blockade in experimental post-ischaemic ARF. In addition, the AII receptor blockade had a harmful effect on this condition, probably due to disturbed autoregulatory renal function. On the other hand, ET and AII receptor blockade in mild NO blockade associated with reperfusion injury, improves the most haemodynamic, biochemical and morphological parameters. CONCLUSIONS: We concluded that experimental post-ischaemic ARF is neither AII nor ET mediated in case of strong NO blockade, but, in more realistic conditions of mild NO deficiency, these peptides represent significant players whose receptor blockade expressed relevant therapeutic potential.     

Low arginine plasma levels do not aggravate renal blood flow after experimental renal ischaemia/reperfusion.

BACKGROUND: Ischaemic renal dysfunction is present in many clinical settings, including cardiovascular surgery. Renal hypoperfusion seems to be the most important pathophysiologic mechanism. Arginine plasma levels are rate limiting for NO synthesis, and low arginine plasma levels are seen after major vascular surgery. OBJECTIVE: to establish the effects of low arginine plasma levels on renal blood flow after renal ischaemia/reperfusion. DESIGN: Wistar rats were used in this unilateral renal ischaemia/reperfusion model. After 70 min of ischaemia, the kidney was reperfused for 150 min. Arginase infusion was used to lower arginine plasma levels. Blood flow measurement was performed at the end of the experiment using radiolabelled microspheres. Additional experiments were performed for histopathology. RESULTS: Arginase efficiently decreased arginine plasma levels to about 50% of normal. There was a lower blood flow in the ischaemic kidney than the contralateral (non-ischaemic) kidney. Lowering arginine plasma levels did not reduce renal blood flow in the ischaemic kidney. Renal histopathology was not influenced by lowered arginine plasma levels. CONCLUSIONS: Lowering arginine plasma levels did not affect blood flow or histology following renal ischaemia and reperfusion.     

Effects of the free radical scavenger dimethyl sulphoxide on experimental normothermic ischaemia of the liver

BACKGROUND/AIMS: This study assessed the effects of intermittent or continuous hepatic ischaemia and reperfusion with or without dimethyl sulphoxide (DMSO) pre-treatment in a rat ischaemic model. METHODS: One hundred and eighty rats were divided into three groups undergoing hepatic ischaemia of a total duration of 60, 90 and 120 min. Each group of rats was subdivided to receive either a continuous Pringle manoeuvre or intermittent liver pedicle clamping of 30 or 15 min. Ten minutes before ischaemia induction, 10 rats from each group were pre-treated with DMSO (500 mg/kg, b.w.) intravenously. RESULTS: With continuous hepatic pedicle clamping, survival rates inversely correlated with the duration of ischaemia, with greater survival in the intermittently clamped groups (p < 0.05). DMSO pre-treatment did not affect survival but resulted in a significant reduction in liver enzyme (aspartate aminotransferase, alanine aminotransferase) release on the first postoperative day following total ischaemic times of 90 min or greater (p < 0.05). After 120 min of total ischaemia, DMSO pre-treatment resulted in higher preservation of adenosine 5'-triphosphate liver content (p < 0.05). CONCLUSION: DMSO may be used to prolong tolerance to inflow occlusion and to limit the adverse effects of ischaemia and reperfusion cycles in an experimental hepatic ischaemia model.     

Effect of sevoflurane preconditioning on ischaemia/reperfusion injury in the rat kidney in vivo

BACKGROUND AND OBJECTIVE: Whereas the protective effect of anaesthetic and ischaemic preconditioning has been described for several organs, it is uncertain whether this mechanism is also effective in the kidney. We compared the effect of preconditioning with sevoflurane and preconditioning with short episodes of ischaemia on renal ischaemia/reperfusion injury in the rat in vivo. METHODS: Fourteen days after right-sided nephrectomy, anaesthetized male Wistar rats were randomly assigned to a sham-operated group (no arterial occlusion, n = 5) or underwent 45 min of left renal artery occlusion (control group, n = 9) followed by 3 days of reperfusion. Two further experimental groups of animals were preconditioned prior to ischaemia either by administering 1 MAC sevoflurane for 15 min followed by 10 min of washout (sevoflurane group, n = 10) or by subjecting the animals to three short episodes of renal ischaemia (ischaemia-preconditioned group, n = 8). Blood creatinine was measured during reperfusion and morphological damage was assessed by histological examination. RESULTS: Baseline creatinine values were similar in all four groups (0.7 +/- 0.2 mg dL-1; mean +/- SD) and remained unchanged in the sham-operated animals after 3 days (0.8 +/- 0.2 mg dL-1). Creatinine levels increased in the ischaemic preconditioning group (3.3 +/- 1.2 mg dL-1) and sevoflurane preconditioning group (4.0 +/- 1.1 mg dL-1) compared to the control group (1.6 +/- 0.6 mg dL-1). Morphological damage was less severe in the control group, i.e. in animals without preconditioning, than in both preconditioning groups. CONCLUSION: Neither sevoflurane nor ischaemic preconditioning preserves renal function or attenuates cell damage in the rat in vivo.     

Prevention of cold ischaemia-reperfusion injury by an endothelin receptor antagonist in experimental renal transplantation.

BACKGROUND: Endothelin (ET) is known to play a role in the pathogenesis of warm ischaemic renal damage, however, little is known about its involvement in renal cold ischaemia. This study was designed to investigate the response of ET after kidney cold ischaemia, and to assess the potential protective effect of bosentan, a dual, non-selective ET(A)/ET(B) receptor antagonist, against cold ischaemia reperfusion injury in a rat model of syngeneic renal transplantation. METHODS: Kidneys from Lewis rats were transplanted, either immediately or after 5 h of cold preservation. After 48 h, contralateral nephrectomy was performed. Rats were organized into three groups: Tr-NoISC, no cold ischaemia; Tr-ISC, 5 h cold ischaemia; and Tr-BOS, 5 h cold ischaemia plus bosentan (100 mg/kg/day, from the day before transplantation until the seventh day post-transplantation). On day 7, plasma and tissue immunoreactive ET (irET), as well as ET mRNA tissue expression, were evaluated. Renal function was measured by means of serum creatinine on days 3, 4, 5 and 7, and by creatinine clearance on day 7. Conventional histology was performed. RESULTS: The ischaemic group had significantly higher plasma irET levels than the non-ischaemic group and significantly lower levels than the bosentan group. Tissue irET levels and ET mRNA expression were similar in the ischaemic and bosentan groups and were higher than in the non-ischaemic group. Throughout the follow-up, serum creatinine was significantly higher in the ischaemic group than in the bosentan group. Moreover, creatinine decreased rapidly in the bosentan group after nephrectomy, whereas it continued to increase for 48 h in the ischaemic group. Kidneys from the ischaemic group showed a higher degree of tubular-cell necrosis and epithelial-cell detachment than kidneys from the bosentan group. CONCLUSIONS: We conclude that cold ischaemia and preservation damage induces an increase in renal ET mRNA and irET expression in the reperfusion phase, contributing both to the deterioration of renal function and to tubular necrosis. Bosentan is effective in protecting kidneys from this cold ischaemia reperfusion damage. Non-selective ET(A)/ET(B) receptor antagonists might be potentially useful in clinical renal transplantation.     

Early renal post-ischaemic tissue damage and dysfunction with contribution of A1-adenosine receptor activation in rat

Aim:   This study investigated the effect of a selective A₁-adenosine receptor (A₁-AR) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), on the renal dysfunction and histological damage induced by ischaemia/reperfusion at an early stage.
Methods:   Pentobarbital anaesthetised rats were prepared for measuring renal functional variables. Ischaemia was induced by bilateral renal artery clamping for 30 min followed by a 4 h reperfusion period. In DPCPX-treated rats, it was infused (i.v.) at 10 µg/kg per min before and after renal ischaemia. Both kidneys were examined using light and electron microscopy.
Results:   The renal ischaemic challenge resulted in major histological and ultrastructural damages, which were associated with decreased creatinine clearance, absolute potassium-excretion and effective free-water reabsorption, but increased fractional sodium-excretion and urine flow during reperfusion period. In DPCPX-treated rats, the histological and ultrastructural damage to the kidneys was improved along with the decrease in creatinine clearance and increase in fractional sodium-excretion being smaller, but the increase in urine flow being larger than those of the non-treated rats, while absolute potassium-excretion and effective free-water reabsorption were equal to those of the sham-operated rats.
Conclusion:   These findings suggest that endogenous activation of A₁-AR contributes to the early development of renal ischaemia/reperfusion injury.     

Postischaemic renal cortical microcirculation and tissue oxygenation in the pig

Porcine and human renal physiology are similar in important aspects. Renal cortical microcirculation and its relation to inulin clearance (CIn) was therefore studied before and after renal ischaemia in 28 pigs under continuous intravenous chlormethiazole-pancuronium anaesthesia. The anaesthesia used provided essential stability in central haemodynamics. The animals were studied for 90 min of reperfusion following 0, 30 or 60 min of renal ischaemia. Twelve of the animals (four were subjected to each duration of ischemia) were also studied 18 h after start of reperfusion. Regional blood flow in the superficial renal cortex was measured by laser Doppler flowmetry (LDF), and tissue oxygenation (PtO2) by surface microelectrode technique. These techniques allow continuous or repeated measurements. During the first 90 min of reperfusion, superficial renal cortical blood flow measured by LDF (Qsrc) underwent considerable temporal variation which followed a certain pattern. Thus, when the renal arterial blood flow was restored after ischaemia, we observed an instant peak in Qsrc followed by a decreasing flow until a minimum value (Qmin) was reached between 3 and 9 min after start of reperfusion (tQmin). Thereafter, Qsrc increased until a maximal value (Qmax) was reached between 11 and 64 min after start of reperfusion (tQmax). The parameters tQmin and tQmax were related to inulin clearance 18 h after start of reperfusion (P less than 0.05 and P less than 0.01, respectively). Thus, it might be possible soon after start of reperfusion--to evaluate the severity of ischaemic damage. This could be useful in the evaluation of different prophylactic strategies, since the full extent of the ischaemic damage, as assessed by clearance determinations, cannot be established until hours later.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ischaemic preconditioning protects the rat kidney from reperfusion injury.

OBJECTIVE: To examine the possible role of ischaemic preconditioning (IPC), an adaptive pathophysiological phenomenon that increases tolerance to ischaemia-reperfusion (I-R) injury, in renal protection when rats are presented with an I-R challenge. MATERIALS AND METHODS: Female Wistar rats (n=36) were divided randomly into four groups: (A) sham-operated controls; (B) IPC only; (C) renal ischaemia (RI) only; and (D) IPC+RI. The left kidney in groups B and D was preconditioned with four cycles of renal artery occlusion lasting 4 min, each occlusion separated by 11 min of reperfusion. The ischaemic insult, applied in groups C and D, comprised 40 min of sustained left renal artery occlusion. In Group D, the IPC cycle was completed 5 min before the start of the ischaemic insult. Differential left renal function was calculated by 99mTc-labelled dimercaptosuccinic acid scintigraphy at 0, 2 and 9 days after treatment, and expressed as a percentage of the total renal uptake. RESULTS: The mean (sem) maximum decrease in left renal function, to 14.5 (4.3)% of the total, occurred on day 2 in Group C. The equivalent value in Group D showed relative preservation of function, at 36.0 (3.5)% (P=0.001 compared with Group C). The mean left renal function improved by day 9, to 39.6 (6.7)% (Group C) and 48.6 (1.5)% (Group D). The mean left renal function in Group B (50.5-53.9%) did not differ from that in controls (49.4-51.4%). CONCLUSION: An IPC regimen applied 5 min before RI in the rat significantly protects it from the functional impairment associated with ischaemia and reperfusion.     

Attenuation of reperfusion injury by renal ischaemic preconditioning: the role of nitric oxide

OBJECTIVE: To determine the effect on nitric oxide (NO) release and renal NO synthase (endothelial, eNOS and inducible, iNOS) activity of renal ischaemia-reperfusion (I/R) in vivo in an animal model, and to examine the possible involvement of NO in ischaemic preconditioning (IP) of the kidney. MATERIALS AND METHODS: In a right-nephrectomized rat model, 42 animals were randomized in four groups: controls; IP-only (4 min of ischaemia followed by 11 min of reperfusion, total of four cycles); renal warm ischaemia (45 min) and 6 h reperfusion; ischaemia (45 min) preceded by IP pretreatment. Serum NO metabolites were assayed 2 and 6 h after ischaemia or the control equivalent. NOS expression in the kidney was detected immuno-histochemically, and damage assessed morphologically in sections stained with haematoxylin and eosin. Kidney function was assessed by the levels of serum creatinine, urea and electrolytes. RESULTS: Compared with before ischaemia, the concentration of serum NO metabolites at 6 h was increased in the IP-only animals (P = 0. 016) and in the IP + I/R group (P = 0.002). There was greater eNOS expression in the IP-only group (P = 0.009) and in the IP + I/R group than in controls (P = 0.050). iNOS expression was greater in the IP-only animals than in the control group (P = 0.050). Histological assessment showed less evidence of cellular damage in IP + I/R animals than in the I/R-alone group (P = 0.020). Serum creatinine level was not significantly different between the IP-only group and the control. There were no differences after 2 h of reperfusion. CONCLUSION: Ischaemic preconditioning has a protective effect on renal structure and function, which may be produced by increased NO release arising from increased NOS expression by 6 h after reperfusion.     

Short-term arterial blood reperfusion of normothermic kidney in renal artery and abdominal aorta reconstructive surgery.

OBJECTIVE: to prevent kidney injury in renal artery and juxta-renal aortic surgery. After 30 min of cross-clamping ischaemia, renal arterial inflow is temporary re-established for 3 min. The aim of the study was to retrospectively analyse the results of this original technique. METHODS: between January 1987 and May 1999, 48 patients underwent kidney short-term arterial blood reperfusion, directly or through the Pruitt-Inahara shunt. The reperfusion was repeated every 30 min of ischaemia, whenever necessary. Fifty control patients underwent <30 min of kidney ischaemia. Patients were assessed by serum creatinine, digital angiography and radioisotope renography using technecium(99). RESULTS: in the study group one patient developed an acute renal failure and died (2% (-95% CI: 0-11%)). In both study and control groups patients showed a similar and moderate but temporary decline in renal function, which returned to preoperative levels after 1 week. CONCLUSIONS: the results of this study indicate that kidney short-term reperfusion may protect renal tissue from prolonged cross-clamping ischaemia (up to 100 min), also in patients considered at high risk for acute renal failure.     

The sequential change of local cerebral blood flow and local cerebral glucose metabolism after focal cerebral ischaemia and reperfusion in rat and the effect of MK-801 on local cerebral glucose metabolism

Summary In order to investigate the time course change of local cerebral blood flow (1CBF) and local cerebral glucose metabolism (1CGM) and the effect of MK-801 (dizocilpine), an NMDA receptor antagonist on glucose metabolism in a middle cerebral artery occlusion-reperfusion model,¹⁴C-Iodo-antipyrine and¹⁴C-Deoxyglucose autoradiographic method have been used. The 1CBF was reduced to 0–10% of the control level in the ischaemic core and to 12–40% in the ischaemic penumbra between 60 and 120 min after the onset of the ischaemia. In the ischaemic core, the marked hyperfusion appeared at 15 min and maintained about 30 to 45 min following reperfusion. In the ischaemic penumbra, the hyperfusion during reperfusion was not found. Hypermetabolism occurred at 30 min and reached to the peak at 60 min after the middle cerebral artery (MCA) occlusion both in the ischaemic core and in the penumbra. The shift from hyper- to hypometabolism was observed during the ischaemia. The reperfusion following 2 hours of MCA occlusion facilitated the decrease of cerebral glucose metabolism in the ischaemic region. The pretreatment of MK-801 (0.4 mg/kg) inhibited both increased glucose metabolism during the ischaemia and decreased glucose metabolism during the reperfusion. The effect of limiting decreased glucose metabolism during the reperfusion by MK-801 was remarkable in the ischaemic penumbra. These findings support the hypothesis that excitation-induced hypermetabolism play a major role in the ischaemic insult following focal cerebral vascular occlusion.     

Effects of diltiazem on postischaemic renal cortical microcirculation in the pig

Diltiazem--a calcium entry blocker--was tested in a porcine model under continuous chlormethiazole-pancuronium anaesthesia as protection against renal failure following 60 min of renal ischaemia. Fourteen pigs were randomly allocated to one experimental (diltiazem and ischaemia) and one control group (only ischaemia) (n = 7 in each). Diltiazem was administered as a continuous intravenous infusion started before the ischaemic insult. In two additional animals diltiazem was given but ischemia was not induced. The postischaemic renal cortical microcirculation was simultaneously investigated in four different regions in the left kidney during the first 4 h of reperfusion. Laser Doppler flowmetry (LDF) was performed in two different regions and measurement of tissue oxygenation was done in two other regions. In the two animals treated with diltiazem without ischaemia, only minor variations in central haemodynamic and renal microcirculatory parameters were evident. In the control group (ischaemia), superficial renal cortical blood flow (Qsrc) decreased from 49 +/- 11 (s.d.) arbitrary units at baseline to 24 +/- 4 arb. units 4 h after start of reperfusion (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Failure of verapamil to protect from ischaemic renal damage

To reassess the reported protective effects of verapamil in renal ischaemia, we perfused the left kidney of uninephrectomized female Wistar rats with verapamil (0.1 and 1.0 mg/kg) immediately prior to clamping the renal artery for 60 min. When compared to controls, both doses of verapamil failed to afford protection with respect to urine flow, plasma creatinine, creatinine clearance or histology 24 and 48 h after ischaemia, whereas the purine nucleotide inosine (200 mg/kg) was partially protective: mean plasma creatinine 48 h after ischaemia (+/- SEM) was 547 +/- 54 mumol/l in controls, 686 +/- 38 mumol/l with 0.1 mg/kg verapamil, 491 +/- 68 mumol/l with 1.0 mg/kg verapamil and 374 +/- 45 mumol/l with inosine (p less than 0.05 vs. controls). Using the same model, the effect of verapamil 1.0 mg/kg on renal blood flow, creatinine clearance, urine flow and arterial pressure was studied in the first 2 h after ischaemia. Although significant amounts of verapamil were present in the kidney during ischaemia as evidenced by decreases in systemic blood pressure and in renal vascular resistance after unclamping the renal artery, the early course of renal failure was not altered when compared to controls. In conclusion, we have been unable to confirm earlier reports of a protective effect of verapamil in this rat model of ischaemic renal failure. If there is such an effect, its demonstration appears to depend on very specific experimental circumstances. Based on the results of this and other studies, verapamil is unlikely to afford an impressive overall benefit in the clinical setting of ischaemic renal failure.