Attenuation of glycerol-induced acute renal failure in rats by trimetazidine and deferoxamine

The pathogenesis of glycerol-induced myoglobinuric acute renal failure involves, among other causes, ischaemia, vascular congestion, and reactive oxygen metabolites. The aim of this study was to investigate the roles of ischaemia and iron-induced oxidative stress by employing trimetazidine, an anti-ischemic drug with an additional antioxidant effect, and deferoxamine, an iron chelator, in glycerol-induced acute renal failure in rats. Five groups of rats were employed in this study: group 1 served as control group, group 2 was given 50% glycerol alone (8 ml/kg i.m.), group 3 was given glycerol plus trimetazidine (3 mg/kg), and groups 4 and 5 were given glycerol plus deferoxamine (50 and 100 mg/kg, respectively). Renal injury was assessed by measuring plasma creatinine and blood urea nitrogen levels and creatinine and urea clearances. The oxidative stress was measured on the basis of the renal malondialdehyde and reduced glutathione levels and the activities of catalase, glutathione reductase, and superoxide dismutase. Glycerol treatment resulted in marked renal oxidative stress and deranged renal functions which significantly improved by trimetazidine and deferoxamine treatments. Deferoxamine, by interacting with Fenton reaction chemistry, and trimetazidine, by its anti-ischaemic and antioxidative properties, protected the kidney against the oxidative stress and the resultant renal dysfunction produced by glycerol. Based on these results, this study points towards renal ischaemia and iron as potential mediators and demonstrates the potential beneficial effects of deferoxamine and trimetazidine in glycerol-induced acute renal failure in rats.     

Cardiovascular responses in rats with glycerol-induced acute renal failure

Autonomic and cardiovascular function were assessed in rats with glycerol-induced acute renal failure (ARF). Rats with ARF had significantly lower mean arterial blood pressure and heart rates and significantly elevated plasma noradrenaline concentrations. The chronotropic responses to right cervical sympathetic and vagal stimulation were diminished in rats with ARF. The pressor and depressor responses to noradrenaline and nitroprusside respectively when expressed as a change in mmHg pressure were significantly reduced in rats with ARF when compared to controls. However, when the depressor responses to nitroprusside were expressed as a percentage fall in basal mean arterial pressure, with the exception of the response to a dose of 10 micrograms kg-1, there were no significant differences between control and uraemic rats. The present findings show that in the rat, changes in cardiovascular responsiveness occur after a brief period of uraemia which are similar to those observed in patients and rats with chronic renal failure.     

Contribution of renal oxygenases to glycerol-induced acute renal failure in the rat

Administration of glycerol produces acute renal failure (ARF) accompanied by profound vasoconstriction. It was hypothesized that impaired arachidonic acid metabolism may contribute to the vasoconstriction through alteration of renal eicosanoids or endothelin-1 or angiotensin II stimulation of renal oxygenases. Arachidonic acid (5, 10, 25 microg) in the control kidney produced increases in perfusion pressure of 15 +/- 9, 18 +/- 8, and 43 +/- 18 mm Hg, respectively. These responses were increased 1.5-fold in glycerol-induced renal failure (p < 0.01). Indomethacin (10 microM), the cyclooxygenase inhibitor, converted arachidonic acid vasoconstriction to epoxide-mediated vasodilator responses, which were unchanged in ARF. In ARF, 5,8,11,14-eicosatetraynoic acid (10 microM), the all-purpose inhibitor of arachidonic acid metabolism; indomethacin (10 microM), a cyclooxygenase inhibitor; 5,8,11-eicosatriyenoic acid (2.5 microM), the 5- and 12-lipoxygenase inhibitor; or aminobenzotriazole (50 mM), the cytochrome P-450 monooxygenase inhibitor, markedly attenuated arachidonic acid-induced vasoconstriction by 73 +/- 11% (p < 0.01), 89 +/- 1% (p < 0.01), 62 +/- 11% (p < 0.01), and 82 +/- 2% (p < 0.01), respectively. In ARF, angiotensin II-induced vasoconstriction was amplified by 67% (p < 0.01). Eicosatetraynoic acid, eicosatriyenoic acid, and aminobenzotriazole reduced these responses by 33 +/- 6% (p < 0.05), 53 +/- 6% (p < 0.01), and 52 +/- 11% (p < 0.05), respectively. Vasoconstriction by endothelin-1 was unchanged in ARF (24 +/- 17%). However, indomethacin attenuated endothelin-1 vasoconstriction by 41 +/- 11% (p < 0.05), whereas eicosatriyenoic acid and aminobenzotriazole were without effect. These data suggest that the increased renal vascular reactivity in ARF in response to arachidonic acid involves a relatively greater production of cyclooxygenase metabolites than monoxygenase- or lipoxygenase-derived eicosanoid metabolites. Furthermore, increased angiotensin II vasoconstriction is predominantly through lipoxygenase and monoxygenase metabolic pathways, whereas for endothelin-1, increased cyclooxygenase-derived vasoconstrictor metabolites play a significant role in its amplified vasoconstrictor effect in glycerol-induced ARF.     

Mechanisms of antibiotic neurotoxicity in renal failure

Neurological complications of antibiotics are relatively common in renal failure. Central nervous system neurotoxicity due to penicillin and beta-lactam antibiotics is best documented with fewer accounts of ototoxicity, peripheral nerve toxicity and neuromuscular blockade. In the context of risk stratification, the goal of this review is to explore the mosaic of factors in renal impairment that may contribute to susceptibility to antibiotic neurotoxicity. Improved knowledge of the pathogenesis of these formidable adverse events among the renal failure subjects should help prevent antibiotic neurotoxicity in the future.     

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.     

Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure

The effect of glycerol-induced acute renal failure on P-glycoprotein expression and function was evaluated in rats. The in vivo function of P-glycoprotein was evaluated by measuring renal secretory and biliary clearance and brain distribution of rhodamine 123 (Rho-123), a P-glycoprotein substrate, under a steady-state plasma concentration. In acute renal failure rats, the P-glycoprotein level increased 2.5-fold in the kidney, but not in the liver and brain. In contrast, P-glycoprotein function in these tissues was suppressed. Interestingly, not only the renal but also the biliary clearance of Rho-123 was correlated with the glomerular filtration rate. In Caco-2 cells, plasma from renal failure rats exhibited a greater inhibitory effect on P-glycoprotein-mediated transport of Rho-123 than did plasma from control rats. In conclusion, P-glycoprotein function was systemically suppressed in acute renal failure, even though the level of P-glycoprotein remained unchanged or rather increased. This may be due to the accumulation of some endogenous P-glycoprotein substrates/modulators in the plasma in disease states.     

Dietary curcumin does not protect kidney in glycerol-induced acute renal failure.

Generation of reactive oxygen species significantly contribute to the pathogenesis of renal injury induced by myoglobin release. The present study was performed to investigate the effects of dietary curcumin, a natural antioxidant isolated from plant Curcuma longa, in an experimental model of myoglobinuric acute renal failure. Rats received curcumin at an oral dose of 100mg/kg/day for 30 days. Renal injury was induced with injection of hypertonic glycerol (10 ml/kg 50% solution) in hind limb muscle with blood urea of 57.8+/-7.2 vs. 7.72+/-1.03 mmol/l and serum creatinine of 444.4+/-61.3 vs. 51.8+/-10.6 micromol/l, in glycerol-induced acute renal failure (ARF) vs. control rats, respectively. After 48 h rats were sacrificed and thiobarbituric acid reactive substance (TBARS), glutathione, carbonyl content and kidney cortex brush border peptidase activities were determined in serum, kidney and liver. Rats that received curcumin in addition to glycerol had significantly lower TBARS in serum but not in kidney and liver. Carbonyl content in kidney and liver was significantly elevated in curcumin and glycerol treated rats and improved in animals treated with curcumin and glycerol together. The activities of kidney cortex enzymes, aminopeptidase N, angiotensinase A and dipeptidyl peptidase IV, were reduced in glycerol as well as in curcumin treated rats. The results obtained in this study provided additional evidence that despite its limited antioxidant activity curcumin did not protect kidney in myoglobinuric model of ARF.     

松花粉对甘油诱导大鼠急性肾衰竭的保护作用

目的：研究松花粉对甘油诱发大鼠急性肾衰竭（acute renal failure,ARF）的保护作用及机制。方法：采用双侧后肢注射50%甘油溶液（10 mL·kg-1）诱发大鼠成急性肾衰竭模型,检测大鼠血清肌酐（Scr）、血清尿素氮（BUN）的含量,肾组织中超氧化物歧化酶（SOD）的活性,谷胱甘肽（GSH）、丙二醛（MDA）的含量,同时测定肾组织中一氧化氮（NO）的含量和诱导型一氧化氮合酶（iNOS）的活性;HE染色观察肾病理组织形态学变化。结果：与空白组大鼠相比,模型组大鼠血清Scr和BUN的含量明显上升,肾组织中SOD的活性和GSH的含量显著降低,MDA的含量显著升高;组织病理检查发现,模型组大鼠肾小管损伤明显,肾皮质细胞部分脱落,肾小球肿胀,间质炎性侵润明显。给予松花粉治疗后,可显著降低ARF大鼠血清Scr和BUN,升高肾组织中SOD的活性、GSH的含量,降低MDA的含量,同时发现,松花粉可明显降低肾组织中NO的含量和iNOS的活性,并显著降低肾组织损伤。结论：松花粉对甘油致大鼠ARF具有治疗作用,其作用机制可能与抑制iNOS的活性,降低体内NO过多产生,降低NO相关的脂质过氧化过程有关。     

Pharmacokinetics and hepatic extraction of metoprolol in rats with glycerol-induced acute renal failure

The aim of the present study was to evaluate the effect of glycerol-induced acute renal failure (ARF) on the pharmacokinetics and hepatic extraction of metoprolol in rats. Experimental ARF in rats was induced by injections of 50% glycerol into the leg muscle (10 ml/kg). Pharmacokinetics and hepatic extraction of metoprolol was evaluated by means of intravenous, intra-intestinal, and intra-portal administration of the drug. The blood metoprolol concentration following intravenous infusion in ARF rats was similar to that in control rats. On the other hand, the blood metoprolol concentration at 5--10 min after intra-intestinal administration in ARF rats was significantly higher than that in control rats, and the oral clearance (CL/F) of the drug was significantly decreased in ARF rats. Hepatic extraction following intra-portal infusion was not altered by glycerol-induced ARF; however, hepatic first-pass extraction of metoprolol was dose-dependent and saturable in both ARF and control rats. These results suggested that the decreased CL/F of metoprolol in rats with glycerol-induced ARF is mainly a result of the increased initial absorption rate in the intestine followed by partial saturation of hepatic first-pass metabolism.     

Effects of caffeic acid phenethyl ester on glycerol-induced acute renal failure in rats

1. Free radicals and nitric oxide (NO) play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). The aim of the present study was to investigate the effects of caffeic acid phenethyl ester (CAPE), an anti-oxidant, on the myoglobinuric ARF induced by intramuscular hypertonic glycerol injection. 2. Thirty rats were divided equally into three groups. Rats in group 1 were given saline and those in groups 2 and 3 were injected with glycerol (10 mL/kg, i.m.). Concomitant and 24 h after glycerol injection, CAPE (10 micromol/kg, i.p.) was administered to group 3 rats. Forty-eight hours after glycerol injection, blood samples and kidney tissues of rats were taken under anaesthesia. 3. Plasma concentrations of urea, creatinine, malondialdehyde (MDA) and NO were determined, as were superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities and MDA levels in kidney tissues. Kidney morphology was also investigated. 4. In the group receiving CAPE, although SOD enzyme activity was found to be increased, we failed to find any protective effect of CAPE on other parameters investigated. Moreover, although CAPE significantly decreased NO levels, it increased plasma concentrations of urea and MDA. 5. We suggest that the effect of CAPE in decreasing NO concentrations may further increase the renal ischaemia in this model. Thus, CAPE may have a worsening rather than beneficial effect under these conditions in this model of ARF.     

Influence of glycerol-induced acute renal failure on the pharmacokinetics of cyclosporin in rats.

Although it is widely believed that renal dysfunction has no effect on the pharmacokinetics of cyclosporin, many clinical reports suggest that renal dysfunction after renal transplantation is closely related to the pharmacokinetics of cyclosporin. To clarify the relationship between renal dysfunction and the pharmacokinetics of cyclosporin, we examined the influence of acute renal failure (ARF) on its pharmacokinetics in glycerol-induced ARF rats. The values of indicators of renal function (serum creatinine, blood urea nitrogen), but not those of indicators of hepatic function, were significantly increased in ARF rats that received glycerol compared with values for control rats. The area under the blood cyclosporin concentration-time curve after oral administration (AUCpo) were 4.976+/-0.847 mghL(-1) for ARF rats and 9.684+/-1.100 mghL(-1) for control rats; AUCpo in ARF was significantly reduced in a manner dependent on renal function. The oral clearance of cyclosporin in ARF and control rats was 1.172+/-0.207 and 0.544+/-0.062Lh(-1) kg(-1), respectively, whereas total body clearance in ARF and control rats was 0.151+/-0.008 and 0.183+/-0.010Lh(-1)kg(-1), respectively. The relative bioavailability of cyclosporin in ARF and control rats was 0.118 and 0.336, respectively. In an in-vitro study using everted sac and liver-slice methods, the apparent first-order rate constants for cyclosporin uptake (k(uptake)) and metabolism (k(metab)) in gut tissues were reduced, whereas k(uptake) and k(metab) in liver were increased. Gastric emptying, measured by use of paracetamol, was significantly reduced in ARF rats. These results suggest that glycerol-induced ARF results in several changes in the pharmacokinetics of cyclosporin in rats. From these results, we conclude that reduction of the absorbed fraction of cyclosporin strongly contributes to the decrease in AUCpo in the presence of ARF.     

Effects of glycerol-induced acute renal failure on tissue glutathione and glutathione-dependent enzymes in the rat

The activities of tissue glutathione (reduced and oxidized) and glutathione-dependent enzymes such as glutathione S-transferase (GSH S-transferase), glutathione reductase (GSSG reductase) and glutathione peroxidase (GSH-Px) were determined for control and uremic rats. Acute renal failure (ARF) was produced by glycerol-water injection. Cytosolic and microsomal GSH S-transferase activity in the kidney was decreased by 38% and 15%, respectively. Hepatic microsomal GSH S-transferase was also decreased by 40% in uremic rats. GSH-Px activity was decreased by 51% in the cytosolic fraction and 33% in the microsomal fraction in the kidney, but was not affected in the liver and whole blood. GSSG reductase activity was also decreased by 48% in the cytosolic fraction in the kidney of uremic rats. In whole blood, however, GSSG reductase activity was increased by 12-fold (0.66 +/- 0.12 mumol NADPH oxidized/min/ml blood in the control; 8.03 +/- 3.29 mumol NADPH oxidized/min/ml blood in uremia). Although the total glutathione concentrations were not significantly affected, the GSSG/GSH ratio, which is an indication of oxidative stress, was significantly increased in the liver and whole blood of uremic rats. In addition to the decreases in hepatic and renal GSH S-transferase activities, which is important in drug disposition, ARF caused decreases in GSSG reductase and GSH-Px activity, which are essential for the protection against lipid peroxidation.     

Protective effect of naringin, a bioflavonoid on glycerol-induced acute renal failure in rat kidney

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was designed to investigate the effect of naringin, a bioflavonoid with antioxidant potential, in glycerol-induced ARF in rats. Five groups of rats were employed in this study, group I served as control, group II was given 50% glycerol (8 ml/kg, intramuscularly), group III, IV, and V were given glycerol plus naringin 100, 200, and 400mg/kg p.o. route, respectively) 60 min prior to the glycerol injection. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine, and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Glycerol treatment resulted in a marked renal oxidative stress and significantly deranged the renal functions. Pretreatment of animals with naringin 60 min prior to glycerol injection markedly attenuated renal dysfunction, morphological alterations, reduced elevated thiobarbituric acid reacting substances (TBARS), and restored the depleted renal antioxidant enzymes. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of naringin in glycerol-induced renal failure in rats.     

Amelioration of glycerol-induced acute renal failure in the rat with 8-cyclopentyl-1,3-dipropylxanthine.

1. Previous studies have shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1- and A2-receptors, can ameliorate the severity of glycerol-induced acute renal failure (ARF) in the rat. In the present study we have examined the effects of an antagonist with selectivity for adenosine A1-receptors (8-cyclopentyl-1,3-dipropylxanthine, CPX) on the development of ARF. 2. In the anaesthetised rat 8-PT (4 mg kg-1, i.v.) and CPX (0.1 mg kg-1, i.v.) antagonised adenosine-evoked responses which are thought to be mediated via A1-receptors (bradycardia and decrease in renal blood flow). The agonist dose-ratio produced by CPX was equal to or greater than that found with 8-PT (heart rate and renal blood flow respectively). The hypotensive response to adenosine which is predominantly due to A2-receptor activation was also antagonised by 8-PT, whereas CPX was a much less effective antagonist of this response. 3. Administration of CPX (0.1 mg kg-1, i.v.; twice daily for two days) significantly attenuated the increase in plasma levels of urea and creatinine, the increased kidney weight and the renal tubule damage observed in rats 2 days following induction of ARF with intramuscular glycerol injection. In addition treatment with CPX significantly enhanced the clearances of inulin and p-aminohippurate. 4. After glycerol injection, the mortality rate over 7 days in untreated and vehicle-treated rats was 43% and 21% respectively. In contrast, all animals treated with CPX survived over the 7 day observation period. 5. These results support the suggestion that adenosine is an important factor in the development of ARF and indicate that this effect of the purine is likely to be mediated via an adenosine A1-receptor.     

Vascular responses to endothelin-1, angiotensin-II, and U46619 in glycerol-induced acute renal failure

Angiotensin II and endothelin-1, major endogenous vasoconstrictors in acute renal failure (ARF), can modulate the effects of each other. This study aimed to evaluate the interaction between these vasoconstrictors in glycerol-induced ARF by evaluating their effects in the isolated perfused kidney in the presence of their respective antagonists. In ARF, angiotensin II (2.5-25 ng) caused an increase in perfusion pressure. Saralasin, 1 microM, a nonselective angiotensin receptor antagonist, reduced these responses by 61+/- 6% (p < 0.05). Surprisingly, SQ29548, 1 microM, a selective PGH2 /thromboxane A2 receptor blocker, also reduced angiotensin II responses (62 +/- 4%; p < 0.05). BQ610 1 microM, an ETA -selective receptor antagonist, was without effect, but BQ788 1 microM, an ETB -selective antagonist, attenuated the response by 70 +/- 4% (p < 0.05). In ARF, in contrast to angiotensin II, vasoconstriction by endothelin-1 (5-25 ng) was diminished. Saralasin further attenuated endothelin-1 response by 65 +/- 2% (p < 0.05), whereas SQ29548 was without effect. BQ788 reduced the responses by 67 +/- 7% (p < 0.05), whereas BQ610 was without effect (42 +/- 30%; p > 0.05). BQ610 and BQ788 combination further reduced vasoconstriction by 89 +/- 3% (p < 0.05). Responses to U46619 were not changed in ARF. However, saralasin and BQ788, but not BQ610, attenuated its vasoconstrictor action. We conclude that vascular responses in ARF may be attributed to enhanced responses to angiotensin II through activation of ETB and/or PGH2 /thromboxane A2 receptors. We also suggest that the vasoconstrictor response to endothelin-1 in ARF is predominantly ETB receptor-mediated.     

Effect of glycerol-induced acute renal failure on the pharmacokinetics of lidocaine after transdermal application in rats

In this study, the effect of glycerol-induced acute renal failure (ARF) on the pharmacokinetics of lidocaine after transdermal application was investigated in rats. Microdialysis method was applied in vitro and in vivo to the abdominal skin of rats. After topical application of 1% lidocaine, the cumulative amount of lidocaine permeated through the excised rat abdominal skin showed parallel effect between normal and ARF rats with no significant difference in the in vitro permeability coefficient of lidocaine between them, while area under the plasma concentration versus time curve of lidocaine in ARF rats increased significantly. The protein binding rate of lidocaine in ARF plasma and the blood vessel permeability to muscle tissues, assessed by beta-D-glucopyranosyl fluorescein isothiocyanate-labeled (FITC) albumin, increased significantly. After intravenous infusion of 5 mg/h/kg lidocaine, both of the total body clearance and the volume of distribution of lidocaine in the ARF rats decreased significantly. These results suggested that renal dysfunction did not have any effect on the skin permeability of lidocaine, but might change the plasma protein binding of drug and blood vessel permeability which led to high plasma concentration of lidocaine.     

Amelioration of glycerol-induced acute renal failure in the rat with 8-phenyltheophylline: timing of intervention

The importance of timing and duration of 8-phenyltheophylline (8-PT) administration in determining its beneficial action in glycerol-induced acute renal failure (ARF) was investigated by examining the effects of a single dose of 8-PT given immediately following (0 h) glycerol injection and at 1 and 3 h after glycerol injection. 8-PT when given at 0 h significantly lowered plasma urea and creatinine concentrations and significantly increased inulin clearance when compared both to untreated animals and those that received the vehicle for the drug. By contrast, 8-PT when administered at 1 h afforded no protective effect on renal function and, when injected at 3 h, the only significant effect was lowered plasma creatinine levels when compared to untreated rats; at this latter time it did not lower plasma urea levels or improve inulin clearance. None of the 8-PT injections attenuated the increase in kidney weight associated with ARF or reduced the kidney damage as assessed by histological examination. The results show that a single administration of 8-PT made immediately following glycerol injection can ameliorate the biochemical and functional indices of impaired renal function, but does not produce an improvement in kidney morphology.     

Effect of the adenosine antagonist 8-phenyltheophylline on glycerol-induced acute renal failure in the rat.

8-Phenyltheophylline (8-PT)(10 mg kg-1) or its vehicle(1 ml kg-1) were administered intravenously or intraperitoneally twice daily over 48 h to rats with acute renal failure (ARF) induced by intramuscular (i.m.) injection of glycerol. Rats treated with 8-PT i.v. had significantly lower plasma urea and creatinine levels at 24 and 48 h compared to untreated animals. The vehicle also reduced plasma urea and creatinine when compared to untreated controls. However, plasma urea levels in 8-PT-treated rats were significantly lower than in vehicle-treated animals at 24 and 48 h after both i.v. and i.p. administration. Plasma creatinine concentrations also tended to be lower in the 8-PT-treated group. [3H]-inulin clearance at 48 h after i.m. glycerol was significantly greater in rats dosed i.p. with 8-PT compared to either untreated or vehicle treated rats. Examination of kidneys taken from rats 48 h after i.m. glycerol showed that 8-PT treatment significantly reduced renal damage and kidney weight compared to the untreated or vehicle-treated groups. In a 7 day study all the rats which received 8-PT i.p. survived whilst in the vehicle and untreated groups the mortality rates were 12 and 21% respectively. In a separate series of experiments 8-PT (10 mg kg-1, i.v. or i.p.) was found to antagonize adenosine-induced bradycardia in conscious rats for up to 5 h. There is no clear explanation for the partial protection afforded by the vehicle but it may be related to either its alkalinity or an osmotic effect produced by the polyethylene glycol component.(ABSTRACT TRUNCATED AT 250 WORDS)