Acute Renal Failure In Rats Research Articles

Recombinant human erythropoietin reduces rhabdomyolysis-induced acute renal failure in rats

BackgroundRhabdomyolysis is one of the causes of acute renal failure. Erythropoietin (EPO) has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of pleiotropic cytoprotective actions. In this study, we used recombinant human erythropoietin (rhEPO) to study the effects on the glycerol-induced rhabdomyolysis with acute renal failure in rats. MethodsTwenty-four rats were divided into three groups as glycerol group, glycerol+EPO group and normal saline+EPO group. Rhabdomyolysis was induced by intramuscular injection of 10mlkg−1 50% glycerol in rats. Ten minutes later, the rats received an intravenous injection of rhEPO (300Ukg−1). Biochemical substances, including haemoglobin, blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and creatine phosphokinase (CPK), were measured at 0, 1, 3, 6, 9, 12, 18, 24 and 48h. Rats were sacrificed 48h later after glycerol administration and the kidneys were removed immediately for pathology and immunohistochemistry (IHC). ResultsIntramuscular injection of glycerol significantly increased blood BUN, Cre, GOT, GPT and CPK levels and induced severe histopathologic damage in the kidneys. Nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) were increased and E-cadherin was decreased after glycerol administration, as detected by IHC in the kidneys. Post-treatment with rhEPO decreased blood BUN, Cre, GOT, GPT and CPK levels, decreased markers of kidney injury and suppressed the release of NF-κB and iNOS after rhabdomyolysis. ConclusionTreatment with rhEPO suppressed the activities of NF-κB and iNOS, decreased BUN, Cre, GOT, GPT and CPK levels, and decreased the markers of kidney injury after rhabdomyolysis. These actions ameliorated rhabdomyolysis-induced acute renal failure in rats.

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

In the evolving paradigm of drug development it is a reasonable strategy to avoid and/or anticipate potential risks in drug development for select drugs by performing in vitro and/or preclinical studies in appropriate animal models. The availability of acute renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic disposition of drugs and associated metabolites in conditions that mimic the pathophysiology of the disease in humans. Such studies may help in drug(s) selection for development, differentiating certain drug classes, and/or arriving at a dose strategy decision in the clinic. Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol (CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The published pharmacokinetic disposition data has unequivocally suggested that ARF conditions leads to decreased renal elimination of the drug and associated metabolites; however, the influence on the overall body clearance is dependent on the propensity of the contribution of renal versus non-renal mechanisms of elimination. In the case studies assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35% of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered exposure, in ARF rat models relative to control rats. Interestingly, ARF can have an overall impact on drug absorption, distribution, metabolism, local transport and biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted with caution during ARF since there is the potential for competiting pathways to co-exist. For instance, due to reduced renal elimination as a result of kidney insult caused by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism. However, there may be instances where uraemic toxins floating in the circulation may block the metabolism and/ or may also retard the absorption process. This review covers: 1) an illustration of a number of case studies providing tabulated information on the key altered pharmacokinetic parameters observed in ARF and the hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption, distribution, metabolism, excretion and efflux transport related changes observed during ARF; 3) a general framework for drug development strategies and 4) a succinct discussion on the overall perspectives of the applicability of ARF rat models.

Effect of Human Umbilical Cord Blood Progenitor Cells Versus Mononuclear Cells on Acute Renal Failure Rat Model

Acute renal failure (ARF) resulting from ischemic or toxic insults remains a major health care problem because of its grave prognosis and the limited effectiveness of available treatment modalities. Current treatment options for ARF are limited to supportive measures and preventive strategies, none of which have been definitively shown to alter mortality. To assess the ability of human umbilical cord blood CD34(+) (HUCB CD34(+)) cells and mononuclear (HUCB MNC) cells to improve renal function of nephrotoxic kidney. ARF was induced in 30 rats by glycerol. After 24 hours, ARF was confirmed by increased blood urea nitrogen (BUN), serum urea and creatinine levels. The rats were divided into 3 groups, group one included 10 rats treated with HUCB CD34(+) cells, group two included 10 rats treated with HUCB MNC and group three included 10 rats treated with normal saline. Five rats were included in the study as a normal control group. Serial measurement of BUN, serum urea and creatinine levels were done every three days throughout the study. To proof homing of HUCB CD34(+) into renal tissue, Y chromosome detection in renal tissue was carried out using Real time polymerase chain reaction (PCR) technique. Four days after the therapy, the renal function of CD34(+) and MNC treated rats improved in comparison to saline treated rats. After 2 weeks of therapy and at the end of the study (28 days), ANOVA test revealed that, there was significant difference between the four studied groups (P=.000). Y chromosomes were detected in kidneys of CD34(+) treated rats and MNC treated rats. HUCB CD34(+) cells and HUCB MNC improve renal function of nephrotoxic kidney with superiority to the HUCB MNC.

Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate: accelerated proliferation and hepatocyte growth factor/c-Met axis

Rats that recovered from mild proximal tubule (PT) injury without renal dysfunction by subtoxic insult, developed partial resistance to subsequent nephrotoxic insult. This partial resistance was associated with reduced renal dysfunction and accelerated PT cell proliferation compared with vehicle treatment as the first insult. Here we assessed the role and potential mechanisms of accelerated PT proliferation in this acquired resistance model. Rats at 14days after recovering from prior mild renal damage induced by 0.2mg/kg uranyl acetate (UA) (subtoxic dose) were rechallenged with 4mg/kg UA (nephrotoxic dose) to establish the acquired resistance model. Cell cycle was inhibited by colchicine to examine the contribution of accelerated PT cell proliferation evaluated by in vivo bromodeoxyuridine (BrdU) labeling on acquired resistance to subsequent nephrotoxic insult. Hepatocyte growth factor (HGF)/c-Met axis and other related factors of cell cycle were analyzed. The acquired resistance to rechallenge injury with nephrotoxic dose of UA in rats recovered from mild renal injury was associated with an earlier increase in BrdU-positive PT cells, accelerated upregulation of HGF mRNA, c-Met mRNA/protein, cyclin D1, phospho-Rb and an earlier phenotypic change of PT cells. Colchicine inhibited PT cell proliferation, reduced the upregulated cyclin D1 and phospho-Rb in the kidney, completely abolishing acquired resistance. Cell cycle progression with upregulated renal HGF/c-Met axis may contribute to the accelerated recovery from acute renal failure in rats that recovered from prior mild renal damage, followed by nephrotoxic insult, resulting in partial acquired resistance.

The effect of glycerol-induced acute renal failure upon cardiac reactivity in the rat: influence of indomethacin treatment and renal pedicle ligation

Cardiac chronotropic responses to isoprenaline, carbachol and electrical stimulation of the cervical sympathetic and vagal nerves were recorded in rats with glycerol-induced acute renal failure (ARF) and control rats. The experiments involving electrical stimulation of cardiac nerves were performed in rats which either had been pretreated with indomethacin (1 mg kg-1 twice daily for 2 days) or had undergone acute bilateral renal pedicle ligation. The findings from this investigation indicate that the reduced chronotropic responses to vagal stimulation in rats with glycerol-induced ARF are due to a reduction in acetylcholine release mediated by prostaglandins possibly originating from the damaged kidneys. The diminished response to cervical sympathetic stimulation results from a decreased postsynaptic response to beta-adrenoceptor stimulation.

Renoprotective effect of Alpiniae oxyphyllae Fructus on ischemia/reperfusion‐induced acute renal failure in rats

The present study was designed to examine whether water extract of Alpiniae oxyphyllae Fructus (AAO) has an effect on renal functional parameters in association with the expression of water channels (AQP-2, 3) and sodium potassium pump (Na,K-ATPase [alpha]1 subunit) in rats with the ischemia/reperfusion-induced acute renal failure (ARF). Polyuria caused by down-regulation of renal AQP-2, 3 in the ischemia/reperfusion-induced ARF rats was markedly restored by administration of AAO (200 mg/kg/day p.o.) with restoring expression of AQP-2, 3 in the kidney. The expression of Na,K-ATPase ¥á1 subunit was also restored in the ischemia/reperfusion-induced ARF rat by administration of AAO. The renal functional parameters including creatinine clearance (Ccr), urinary sodium excretion, urinary osmolality, and solute-free reabsorption were also markedly restored in ischemia-ARF rats by administration of AAO. Periodic acid Schiff (PAS) staining showed that administration of AAO improved tubular damage I/R-induced ARF. Taken together, the present study suggested that administration of AAO ameliorates the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF, through the restoring of AQP-2, 3 and Na,K-ATPase.

Role of Endothelin‐1 in Ischemic Acute Renal Failure in Rats

The role of endothelin-1 in ischemic acute renal failure in rats is described. After 45 min of ischemia, mean blood pressure was increased by 11% and renal blood flow (RBF) and renal surface blood flow (RSBF) rates were reduced by about 30% resulting in a 70% increase in renal vascular resistance (RVR) compared with nonischemic control rats. Higher levels of endothelin-1 were also found in the kidneys and plasma of ischemic rats. Endothelin-1-induced ischemia seems to play a significant role in the pathogenesis of acute renal failure. During reperfusion, injection of endothelin-1 (0.1–0.3 nmolkg−1) into post-ischemic rats did not affect RBF, RSBF or RVR. However, injection of the α-stimulant, 1-phenylephrine (1–10μg kg−1), dose-dependently reduced RBF and RSBF, regardless of whether renal ischemia had occurred. The endothelin-1 insensitivity of post-ischemic rats may be due to inactivation of the vasocontractile systems or activation of the vasodilative systems.

Pharmacological investigations of Punica granatum in glycerol-induced acute renal failure in rats

Objective:The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats.Materials and Methods:The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury.Results:Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction.Conclusion:Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway.

Effect ofCuscuta chinensison Renal Function in Ischemia/Reperfusion-Induced Acute Renal Failure Rats

The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na(+), K(+), Cl(-), creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na,K-ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K-ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.

Ameliorative effect of flunarizine in cisplatin-induced acute renal failure via mitochondrial permeability transition pore inactivation in rats

This study was aimed to evaluate the protective effect of flunarizine on cisplatin-induced acute renal failure. Administration of cisplatin (6 mg/kg, i.p. on day 6) significantly increased serum blood urea nitrogen and creatinine, urinary N-acetyl β-D-glucosaminidase, tissue thiobarbituric acid reactive substances and total calcium whereas, decreased body weight, fractional excretion of sodium, creatinine clearance tissue-reduced glutathione, mitochondrial cytochrome c oxidase, and ATP levels were observed in acute renal failure rats. Moreover, cisplatin produced histopathological changes in the renal tissue. Furthermore, flunarizine (100, 200, and 300 μM/kg, p.o., for six consecutive days) was administered to evaluate its therapeutic potential in acute renal failure, and the results were compared with cyclosporin A (50 μM/kg, p.o., for six consecutive days) as a reference drug. Flunarizine resulted in the attenuation of cisplatin-induced renal dysfunction, oxidative stress marker, mitochondrial damage, and histopathological changes in rats. Medium and higher doses of flunarizine produced significant renal protective effect which was comparable to cyclosporin A. The results of this study clearly revealed that flunarizine protected the kidney against the nephrotoxic effect of cisplatin via mitochondrial permeability transition pore inactivation potential.

Altered electrolyte handling of the choroid plexus in rats with glycerol‐induced acute renal failure

The altered electrolyte handling of the choroid plexus was investigated in rats with acute renal failure (ARF) using lithium and rubidium as surrogate markers for sodium and potassium, respectively. Firstly, the transport of these two markers from the plasma to cerebrospinal fluid (CSF) was evaluated after they were concurrently injected into the femoral vein. As a result, their disposition from the plasma to CSF was shown to decrease in ARF rats, but the relationship profile between those two markers was not different from that observed in normal rats, indicating that the decreased disposition of lithium and rubidium occurs without affecting the stoichiometric balance. To clarify the mechanisms accounting for the decreased disposition, an inhibition study was then performed. When bumetanide, an inhibitor of the Na(+) /K(+) /2Cl(-) co-transporter, was directly introduced into the cerebroventricle prior to lithium and rubidium being intravenously administered, a marked increase in the markers' disposition was observed. However, such an increased disposition did not occur when bumetanide was injected into the femoral vein. Other inhibitors, such as amiloride for the Na(+) /H(+) exchanger and ouabain for Na(+) /K(+) -ATPase, did not show any effects on marker disposition regardless of the inhibitor being administered into either the cerebroventricle or femoral vein. These findings suggest that the decreased marker disposition in ARF rats is due to an increased efflux process of the choroid plexus mediated by the Na(+) /K(+) /2Cl(-) co-transporter. That is, electrolyte efflux from the CSF to plasma increases, and thereby the electrolyte influx from the plasma to CSF is counteracted.

Renal protective effect of extract from peanut shell on acute renal failure rats: role of NOS-IR in locus coeruleus

Renal protective effect of extract from peanut shell on acute renal failure rats: role of NOS-IR in locus coeruleus

Characterization of renal hemodynamic and structural alterations in rat models of renal impairment: role of renal sympathoexcitation

Renal sympathetic innervation plays an important role in the control of renal hemodynamics and may therefore contribute to the pathophysiology of many disease states affecting the kidney. Thus, the present study aimed to investigate the role of the renal sympathetic nervous system in the early deteriorations of renal hemodynamics and structure in rats with pathophysiological states of renal impairment. Anesthetized Sprague Dawley (SD) rats with cisplatin-induced acute renal failure (ARF) or streptozotocin (STZ)-induced diabetes mellitus (DM) were subjected to a renal hemodynamic study 7 days after cisplatin and STZ administration. During the acute study, renal nerves were electrically stimulated, and responses in renal blood flow (RBF) and renal vascular resistance (RVR) were recorded in the presence and absence of renal denervation. Post mortem kidney collection was performed for histopathological assessment. In innervated ARF or DM rats, renal nerve stimulation produced significantly lower (all p<0.05, vs. innervated control) renal vasoconstrictor responses. These responses were markedly abolished when renal denervation was performed (all p<0.05); however, they appeared significantly higher compared with denervated controls (all p<0.05). Kidney injury was suppressed in denervated ARF, while, irrespective of renal denervation, renal specimens from DM rats were comparable to controls. Renal sympathoexcitation is involved in the pathogenesis of the renal impairment accompanying ARF and DM, and may even precede the establishment of an observable renal injury. There is a possible enhancement in the renal sensitivity to intrarenal norepinephrine following renal denervation in ARF and DM rats.

Role of the renal sympathetic nervous system in mediating renal ischaemic injury-induced reductions in renal haemodynamic and excretory functions

We investigated the role of renal sympathetic innervation in the deterioration of renal haemodynamic and excretory functions during the early post-ischaemic phase of renal ischaemia/reperfusion injury. Anaesthetised male Sprague-Dawley rats were subjected to unilateral renal ischaemia by clamping the left renal artery for 30 min followed by reperfusion. Following acute renal denervation clearance experiments were performed. In a different set of experiments, the renal nerves were electrically stimulated at increasing frequencies and responses in renal blood flow and renal vascular resistance were recorded. Denervated post-ischaemic acute renal failure (ARF) rats showed higher urine flow rate, absolute and fractional sodium excretions, urinary sodium to urinary potassium, glomerular filtration rate and basal renal blood flow but lower basal renal vascular resistance (all p < 0.05 vs innervated ARF rats). Potassium excretion was significantly lower in denervated group as per fractional (p < 0.05 vs innervated ARF rats) but not absolute potassium excretion (p > 0.05 vs innervated ARF rats). The rise in mean arterial pressure and renal vasoconstrictor response to renal nerve stimulation were blunted in denervated ischaemic ARF rats (all p < 0.05 vs innervated ARF rats). Renal histopathology in denervated ARF rats manifested a significantly lower medullary congestion, inflammation and tubular injury compared to innervated counterparts (p < 0.05 vs innervated ARF rats). The findings strongly suggest the involvement of renal sympathetic tone in the post-ischaemic events of ischaemic ARF, as the removal of its action to a degree ameliorated the post-ischaemic renal dysfunctions.

Adenosinergic Modulation Of The Imidazoline I1‐Receptor‐Dependent Hypotensive Effect Of Ethanol In Acute Renal Failure

We recently reported that ethanol lowers blood pressure (BP) in rats with acute renal failure (ARF) via facilitation of sympathoinhibitory pathways of central imidazoline I1‐receptors. This study investigated whether adenosine receptor subtypes modulate the ethanol‐I1‐receptor interaction. The effect of selective blockade of adenosine A1, A2A, or A2B receptors on hemodynamic responses to consecutive administration of moxonidine, I1‐receptor agonist, and ethanol was determined in the glycerol model (10 ml/kg, i.m.) of ARF. Ethanol (1 g/kg i.v.) elicited significant decreases and increases in BP and heart rate (HR), respectively, in ARF rats. Prior exposure to moxonidine abolished the hypotensive but not the tachycardic effect of ethanol. The ability of moxonidine to abolish ethanol hypotension disappeared after selective blockade of adenosine A1 or A2A receptors with 8‐Cyclopentyl‐1,3‐dipropylxanthine and 8‐(3‐chlorostyryl) caffeine, respectively. In contrast, the moxonidine‐ethanol interaction was not affected in presence of alloxazine, a selective A2B antagonist or 8‐phenyltheophylline, a nonselective adenosine receptor antagonist. These findings suggest that alterations caused by moxonidine in adenosine A1 and A2A receptor signaling function to offset the I1‐receptor‐dependent hypotensive action of ethanol in ARF rats.

Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA2 mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23 ± 3%; p < 0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60 ± 20%; p < 0.05) but reduced AngII vasoconstriction (51 ± 11%; p < 0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB2 levels in ARF. Candoxatril reduced plasma AngII by 34 ± 4% (p < 0.05) in ARF which was ∼3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na+ and creatinine excretion in ARF by 73 ± 9% and 33 ± 2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.

Effect of Cuscuta chinensis on renal function in ischemia/reperfusion‐induced acute renal failure rats

The kidneys play the central role in regulating the water, ion composition and excrete metabolic waste products into the urine. Cuscuta chinensis has been known as an important traditional Chinese medicine for controlling urination. Thus, we designed to examine whether aqueous extract of Cuscuta chinensis (ACC) has an effect on renal function parameters in ischemia/reperfusion (I/R)‐induced acute renal failure (ARF) rats. Administration of ACC (250 mg/kg/day) for 4 days showed that renal functional parameters including urinary excretion rate, osmolality, Na+, K+, Cl−, creatinine clearance, solute‐free water reabsorption and blood urea nitrogen were significantly recovered in I/R‐induced ARF. Periodic acid Schiff (PAS) staining showed that administration of ACC improved tubular damage I/R‐induced ARF. In immunoblot and immunohistological examination, I/R‐induced ARF decreased the expressions of water channel (AQP 2, 3) and sodium potassium pump (Na,K‐ATPase) in renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K‐ATPase expression. Therefore, these data indicate that administration of ACC ameliorates regulating the urine concentration and renal functions in rats with I/R‐induced ARF.

The increased intestinal absorption rate is responsible for the reduced hepatic first-pass extraction of propranolol in rats with cisplatin-induced renal dysfunction.

The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)). ARF induced a significant increase in blood propranolol concentration after intra-intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg(-1) was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg(-1) dose was 54.7% and 81.4% in control and ARF rats, respectively. In contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first-pass extraction (E(h)) was dose-dependent and saturable: E(h) of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg(-1), respectively, and E(h) in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg(-1), respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism.

Benidipine Inhibits Apoptosis During Ischaemic Acute Renal Failure in Rats

We have investigated the effects of benidipine (hydrochloride), a calcium antagonist, against ischaemic acute renal failure in rats. Using histological examination, we studied whether the inhibition of apoptosis was associated with the protective effects of benidipine on the ischaemic renal injury. Acute renal failure was induced by the unilateral clamping of the left renal artery for 60 min, followed by reperfusion and contralateral nephrectomy. Drugs were given intravenously 5 min before the unilateral clamping. Prophylactic administrations of benidipine (10 microg kg(-1), i.v.) significantly ameliorated the development of renal failure as estimated by the measurements of serum creatinine and blood urea nitrogen 24 h after the reperfusion. Amlodipine (besilate, 100 and 300 microg kg(-1), i.v.) tended to attenuate renal dysfunction. Lisinopril (300 and 1000 microg kg(-1), i.v.), an angiotensin converting enzyme inhibitor, was ineffective in this acute renal failure model. Histological examination using the terminal transferase-mediated dUTP-biotin nick end-labelling (TUNEL) method to detect apoptotic cells revealed that the TUNEL-positive tubular epithelium was prominent in the renal cortex 24 h after the reperfusion. The TUNEL-positive cells were significantly reduced by pretreatment with benidipine. The results demonstrate that benidipine can ameliorate the ischaemic acute renal failure in rats and suggest that the renoprotective effect of benidipine was at least partly attributable to the reduction of apoptosis in tubular epithelial cells.

Effect of Acute Renal Failure on the Disposition of Cefoperazone

The effect of acute renal failure on the disposition of cefoperazone was investigated. Rats, 3 days after uranyl nitrate treatment, were used to model acute renal failure. Although plasma-protein binding of cefoperazone decreased significantly in acute renal failure compared with control rats, the plasma clearance of total (bound plus unbound) drug after intravenous administration (50 mg kg(-1)) did not differ significantly between the two groups (5.61+/-2.37 mL min(-1) for control and 4.75+/-2.82 mL min(-1) for acute renal failure). Consequently the plasma clearance of the unbound drug in acute renal failure (6.14+/-1.16 mL min(-1)) was significantly lower than in control rats (15.6+/-3.7 mL min(-1), P < 0.025). Plasma clearance of the drug (both total and unbound) was also dependent on bile flow, and clearance of the unbound drug in acute renal failure rats was lower than in control rats with identical bile flow rates. To examine the mechanism of reduced unbound cefoperazone clearance, an in-vitro experiment using a simultaneous perfusion system of rat liver and kidney was performed. By changing perfusate plasma protein from bovine serum albumin to human serum albumin, the plasma clearance of the total cefoperazone changed to one-sixth in proportion to the unbound cefoperazone in the perfusate plasma. On the other hand, the plasma clearance of the total and unbound drug in acute renal failure rats decreased significantly compared with controls. These results demonstrate that the plasma clearance of unbound cefoperazone, which is mainly eliminated by the liver, decreased in acute renal failure in rats, probably due to changes in hepatic transport.