Ten patients on long term lithium therapy (mean four years, range 1-10.5 years) were subjected to various renal, thyroid, haematological, cardiac and endocrine tests. There was impaired urinary concentrating ability in seven subjects, which was not responsive to vasopressin stimulation, suggesting a partial nephrogenic diabetes insipidus. Nine subjects had metabolic acidosis with higher urinary pH than expected suggesting presence of acidification defect in the kidney. No significant change in renal function, thyroid function, ECG or haematological parameters were detected. Our findings concur with previous reports from the West regarding the safety of lithium administration.
1. In vitro studies of non-specific histidine decarboxylase activity was low or absent in control guinea-pigs and unchanged 9 or 27 hr after chlorpromazine (CPZ) injection intraperitoneally. 2. However, specific histidine decarboxylase activity was found in the control tissues and was increased 9 hr but not 27 hr after CPZ injection.
The effect of tocotrienol on the activities of glutathione S-transferases (GSTs), glutathione reductase (GR) and glutathione peroxidase (GPx) in rats given 2-acetylaminofluorene (AAF) was investigated over a 20 week period. Liver and kidney GST and liver GR activities were significantly increased after AAF administration. Kidney GPx activities were significantly affected; activity assayed with cumene hydroperoxide (cu-OOH) was increased but activity assayed with H2O2 was reduced. Supplementation of the diet with tocotrienol in the AAF-treated rats reduced the increase in enzyme activities. Tocotrienol on its own had no effect on the enzyme activities.
Increasing animal evidence support an important facilitatory interaction between angiotensin II and norepinephrine within the kidney. This angiotensin II/norepinephrine interaction was investigated in man by examining the effect of enalapril pretreatment (5 mg for 5 days) on the renal response to a low non-pressor dose of intravenous tyramine 4 micrograms/kg/min for 120 min in 8 healthy subjects undergoing water diuresis. Tyramine is an indirect sympathomimetic agent which causes neuronal release of norepinephrine. Enalapril and tyramine, alone and in combination, had no effect on glomerular filtration, effective renal plasma flow or sodium excretion. Tyramine caused a significant increase in urinary flow rate (p < 0.05) but this was not influenced by enalapril pretreatment. The lack of effect of enalapril on the renal response to tyramine contrasts with a previous study which examined the effect of enalapril on the renal response to circulating norepinephrine. This may suggest that enalapril affect renal function only when there is renal vasoconstriction (as with norepinephrine) and not when renal blood flow is unchanged (as with tyramine).
The effect of phenobarbitone against signal grass (Brachiaria decumbens) toxicity was studied in 26 male crossbred sheep. Grazing on signal grass significantly decreased the concentration of cytochrome P-450 and the activity of drug metabolizing enzymes, viz. aminopyrine-N-demethylase, aniline-4-hydroxylase, UDP- glucuronyltransferase and glutathione-S-transferase in liver and kidneys of affected sheep.Oral administration of phenobarbitone (30 mg/kg body weight) for five consecutive days before grazing on B. decumbens pasture, and thereafter, for three consecutive days every two weeks, resulted in significant increases in hepatic and renal activities of drug-metabolizing enzymes. The induction of drug metabolizing activity in sheep grazing on signal grass group was found to be lower than in animals given phenobarbitone alone. Induction by phenobarbitone provided a degree of protection against the toxic effects of B. decumbens as indicated by the delay in the appearance of signs of toxicity. Furthermore, these were much milder compared to those in the sheep not treated with phenobarbitone. The present study suggests that phenobarbitone-type cytochrome P-450 isoenzyme-induction may increase resistance against signal grass (B. decumbens) toxicity in sheep.
The aim of this study was to investigate the effect of altered thyroid status on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD type 1) and type 2 (11beta-HSD type 2) bioactivity in rat kidney and colon. Male Sprague-Dawley rats (250 g) were treated with either L-thyroxine (T4) or propylthiouracil (PTU) for 4 weeks. Blood were then analysed for serum thyroxine, sodium (Na+) and potassium (K+). The kidneys and colon were assayed for 11beta-HSD type 1 and 11beta-HSD type 2 bioactivity. In T4 treated rats the serum thyroxine was significantly elevated (p<0.05) whilst PTU decreased serum thyroxine significantly (p<0.001) compared to controls. Serum Na+ and K+ were within normal limits. There were no significant changes in 11beta-HSD type 1 bioactivity in both treatment groups compared to controls. However, the 11beta-HSD type 2 bioactivity in rats given thyroxine was significantly higher in the colon (p<0.003) compared to controls. We conclude that altered thyroid status had no effect on 11beta-HSD type 1 bioactivity but 11beta-HSD type 2 bioactivity was elevated in the colon of rats given supplementary thyroxine.
The effects of bisphenol A and nonylphenol on pubertal development in the intact juvenile/peripubertal male Sprague-Dawley rats was observed in this study from PND23-52/53. Two groups of rats were administered orally with either 100 mg/kg body weight of nonylphenol or bisphenol A. Another group of rats were administered orally with a mixture of 100 mg/kg body weight of nonylphenol and bisphenol A. Control group was administered with the vehicle of Tween-80 with corn oil (1:9 v/v). Observations made in this study included growth, age at preputial separation, thyroid, liver, testis and kidney weight and histology, epididymal and seminal vesicle plus coagulation gland weight. Nonylphenol and bisphenol A have been observed to cause delay in puberty onset as well as testicular damage in the treatment groups when compared to the control; spermatogenesis was affected in most treated rats. Bisphenol A also caused the enlargement of the kidney and hydronephrosis. Administration of nonylphenol and bisphenol A as a mixture has caused less than additive effects.
An earlier study showed that des-aspartate-angiotensin I (DAA-I) attenuated the pressor action of angiotensin III in aortic rings of the spontaneously hypertensive rat (SHR) but not the normotensive Wistar Kyoto (WKY) rat. The present study investigated similar properties of DAA-I in isolated perfused kidneys and mesenteric beds of WKY and SHR. In the renal vasculature, angiotensin III induced a dose-dependent pressor response, which was more marked in the SHR than WKY in terms of significant greater magnitude of response and lower threshold. DAA-I attenuated the pressor action of angiotensin III in both the WKY and SHR. The attenuation in SHR was much more marked, occurring at doses as low as 10(-15) M DAA-I, while effective attenuation was only seen with 10(-9) M in WKY. The effects of DAA-I was not inhibited by PD123319 and indomethacin, indicating that its action was not mediated by angiotensin AT2 receptors and prostaglandins. However, the direct pressor action of angiotensin III in the SHR but not the WKY was attenuated by indomethacin suggesting that this notable difference could be due to known decreased response of renal vasculature to vasodilator prostaglandins in the SHR. Pressor responses to angiotensin III in the mesenteric vascular bed was also dose dependent, but smaller in magnitude compared to the renal response. The responses in the SHR, though generally smaller, were not significantly different from those of the WKY. This trend is in line with the similar observations with angiotensin III and II by other investigators. In terms of the effect of DAA-I, indomethacin and PD123319 on angiotensin III action, similar patterns to those of the renal vasculature were observed. This reaffirms that in the perfused kidney and mesenteric bed, where the majority of the vessels are contractile, femtomolar concentrations of DAA-I attenuates the pressor action of angiotensin III. The attenuation is not indomethacin sensitive and does not involve the angiotensin AT2 receptor. The findings suggest that DAA-I possesses protective vascular actions and is involved in the pathophysiology of hypertension.
The effects of indomethacin and nabumetone on urine and electrolyte excretion in conscious rats were examined. Male Sprague-Dawley rats were housed individually for a five-week duration, consisting of acclimatization, control, experimental, and recovery phases. During the experimental phase, rats were given either indomethacin (1.5 mg . kg(-1) body weight . day(-1) in 0.5 ml saline, n = 10), nabumetone (15 mg . kg(-1) body weight . day(-1) 0.5 ml saline, n = 10), or 0.5 ml saline alone (n = 10) for a period of two weeks. Water and food intake, body weight, urine output, and electrolyte excretions were estimated. Data were analyzed using two-way ANOVA. Urine output in the indomethacin- and nabumetone-treated groups was not different from the controls, but was significantly different between the drug-treated groups (P<0.01). Sodium, potassium, calcium, and magnesium excretions were not different between nabumetone-treated and control rats. However, sodium and potassium excretion was significantly lower in rats receiving indomethacin when compared to the control rats. Calcium and magnesium outputs, although did not differ from the controls, nevertheless decreased significantly with indomethacin (P<0.01). It appears that indomethacin and nabumetone when given at maximum human therapeutic doses may affect urine and electrolyte output in conscious rats.
Systemic Lupus Erythematosus (SLE) is a multisystemic autoimmune disease with renal involvement being one of the most frequent and serious manifestations of the disease. The aim of the study is to analyze the treatment and renal outcome of patients with lupus nephritis (LN) WHO class III and IV on cyclophosphamide (CYC). We retrospectively identified 41 patients with biopsy proven LN who was given either oral or intravenous CYC. The male: female ratio was 4:37; with a mean age of 31.7 +/- 9.8 years at presentation. 36 patients (87.8%) had LN class IV and only five patients (12.2%) with LN class III. The mean serum creatinine at presentation was 87.4 +/- 37.2 micromol/L with mean follow-up of 84 +/- 78 months. A total of 30 patients (73.2%) completed 12 courses of IV CYC and one patient (2.4%) completed three months of oral CYC. 71.0% (n = 22) had complete response (CR), 25.8% (n = 8) had partial response and 3.2% (n = 1) had no response (NR). Of the remaining 11 patients, two patients (4.9%) died during the treatment, three patients (7.3%) defaulted treatment and five patients (12.2%) are still receiving ongoing treatment. Presence of hypertension (p < 0.003) and evidence of chronicity on renal biopsy (p < 0.016) were significantly correlated with the progressive deterioration of renal function in our population. In conclusion, hypertension and evidence of chronicity on renal biopsy, proved to be risk factors for progressive renal impairment in our study population. The achieved global outcome can be considered good.
Study site: Hospital Ipoh, Ipoh, Perak, Malaysia
Angiotensin 1-7, a heptapeptide derived from metabolism of either angiotensin I or angiotensin II, is a biologically active peptide of the renin-angiotensin system. The present study investigated the effect of angiotensin 1-7 on the vasopressor action of angiotensin II in the renal and mesenteric vasculature of Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and streptozotocin-induced diabetic rats. Angiotensin II-induced dose-dependent vasoconstrictions in the renal vasculature. The pressor response was enhanced in the SHR and reduced in the streptozotocin-diabetic rat compared to WKY rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in the renal vasculature of WKY and SHR rats. However, the ability to reduce angiotensin II response was diminished in diabetic-induced rat kidneys. The effect of angiotensin 1-7 was not inhibited by 1-[(4-(Dimethylamino)-3-methylphenyl] methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate (PD123319), an angiotensin AT(2) receptor antagonist. (D-ALA(7))-Angiotensin I/II (1-7) (D-ALA) (an angiotensin 1-7 receptor antagonist), indomethacin (a cyclo-oxygenase inhibitor), and N(omega)-Nitro-L-Arginine Methyl Ester (L-NAME)(a nitric oxide synthetase inhibitor) abolished the attenuation by angiotensin 1-7 in both WKY rats and SHR, indicating that its action is mediated by angiotensin 1-7 receptor that is either coupled to the release of prostaglandins and/or nitric oxide. The vasopressor responses to angiotensin II in mesenteric vasculature bed was also dose-dependent but smaller in magnitude compared to the renal vasculature. The responses to angiotensin II were relatively smaller in SHR but no significant difference was observed between WKY and streptozotocin-induced diabetic rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in WKY, SHR and diabetic-induced mesenteric bed. The attenuation was observed at the lower concentrations of angiotensin II in WKY and diabetic-induced rats but at higher concentrations in SHR. Similar observation as in the renal vasculature was seen with PD123319, D-ALA, and L-NAME. Indomethacin reversed the attenuation by angiotensin 1-7 only in the SHR mesenteric vascular bed. The present findings support the regulatory role of angiotensin 1-7 in the renal and mesenteric vasculature, which is differentially altered in hypertension and diabetes.
The pathogenesis of cisplatin-induced renal failure is related to reduced renal blood flow due to severe tubular damage and enhanced renovascular resistance. It is also known that alpha(1)-adrenoceptors, the major subtype of alpha-adrenoceptors in renal vasculature play the pivotal role in regulating renal hemodynamics. With this background, we have hypothesized that the altered renal hemodynamics and enhanced renovascular resistance in cisplatin-induced renal failure might be caused by the altered alpha-adrenergic responsiveness with a possible involvement of alpha(1)-adrenoceptors in the renal vasculature. In a unique experimental approach with anesthetized rats, this study has therefore examined if there is any shift in the renovascular responsiveness to renal nerve stimulation and a series of alpha-adrenergic agonists in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats with cisplatin-induced renal failure in comparison with their body weight-matched normal controls. Thirty-two male rats of both WKY (n=16) and SHR (n=16) origin with body weight 236+/-7.9 g received cisplatin (5mg/kg i.p.). The renal failure was confirmed in terms of significantly reduced renal blood flow, reduced creatinine clearance, increased fractional excretion of sodium, increased kidney index (all P<0.05) and tubular damage. After 7 days of cisplatin, the overnight fasted rats were anesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and renal vasoconstrictor experiments were done. The changes in the vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by electrical renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine and methoxamine. It was observed that in the cisplatin-treated renal failure WKY and SHR rats there were significant (all P<0.05) reductions in the renal blood flow along with significantly (P<0.05) higher renal adrenergic responsiveness as compared with their non-renal failure controls. The data showed that in the renal failure WKY and SHR rats, the altered renal hemodynamics might be caused by an augmented renal adrenergic responsiveness. The results obtained further led us to suggest that the augmented renal adrenergic responsiveness in the cisplatin-induced renal failure rats were possibly mediated by the alpha(1)-adrenoceptors.
1 The present study investigated the effect of streptozotocin-induced diabetes on alpha(1)-adrenoceptor subtypes in rat renal resistance vessels. 2 Studies on renal haemodynamics were carried out 7 days after the last streptozotocin. Changes in renal blood flow were recorded in response to electrical stimulation of the renal nerve (RNS) and a range of adrenergic agonists; noradrenaline (NA), phenylephrine (PE) and methoxamine (MTX), either in the absence or the presence of nitrendipine (Nit), 5-methylurapidil (MEU), chlorethylclonidine (CEC) or BMY 7378. 3 In non-diabetic animals, Nit, MEU and BMY 7378 significantly attenuated renal vasoconstriction induced by adrenergic agonists, while CEC showed a significant accentuation in RNS-induced responses without having a significant effect on responses to adrenergic agonists. In diabetic rats, renal vasoconstriction was also significantly reduced in Nit-, MEU- and BMY 7378-treated groups and CEC potentiated RNS-induced contractions caused a change similar to that observed in non-diabetic rats. BMY 7378 significantly (P < 0.05) attenuated the PE- and MTX-induced vasoconstrictions but did not cause any significant (P > 0.05) alteration in the RNS- and NA-induced responses. 4 The results showed functional co-existence of alpha(1A)- and alpha(1D)-adrenoceptors in the renal vasculature of SD rats irrespective of the presence of diabetes. A possible minor contribution of prejunctional alpha-adrenoceptor subtype has also been suggested in either experimental group, particularly possible functional involvement of alpha(1B)-adrenoceptor subtypes in non-diabetic SD rats.
The aim of the present study was to investigate the effectiveness of transforming growth factor (TGF)-beta1 antisense oligodeoxynucleotides (ODN) in ameliorating deteriorated kidney function in rats with puromycin-induced chronic renal failure (CRF).
Curcumin (diferuloylmethane), a biologically active ingredient derived from rhizome of the plant Curcuma longa, has potent anticancer properties as demonstrated in a plethora of human cancer cell lines/animal carcinogenesis model and also acts as a biological response modifier in various disorders. We have reported previously that dietary supplementation of curcumin suppresses renal ornithine decarboxylase (Okazaki et al. Biochim Biophys Acta 1740:357-366, 2005) and enhances activities of antioxidant and phase II metabolizing enzymes in mice (Iqbal et al. Pharmacol Toxicol 92:33-38, 2003) and also inhibits Fe-NTA-induced oxidative injury of lipids and DNA in vitro (Iqbal et al. Teratog Carcinog Mutagen 1:151-160, 2003). This study was designed to examine whether curcumin possess the potential to suppress the oxidative damage caused by kidney-specific carcinogen, Fe-NTA, in animals. In accord with previous report, at 1 h after Fe-NTA treatment (9.0 mg Fe/kg body weight intraperitoneally), a substantial increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts in renal proximal tubules of animals was observed. Likewise, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and protein reactive carbonyl, an indicator of protein oxidation, were also increased at 1 h after Fe-NTA treatment in the kidneys of animals. The prophylactic feeding of animals with 1.0% curcumin in diet for 4 weeks completely abolished the formation of (i) HNE-modified protein adducts, (ii) 8-OHdG, and (iii) protein reactive carbonyl in the kidneys of Fe-NTA-treated animals. Taken together, our results suggest that curcumin may afford substantial protection against oxidative damage caused by Fe-NTA, and these protective effects may be mediated via its antioxidant properties. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.
Cyclosporine A (CsA), a calcineurin inhibitor produced by the fungi Trichoderma polysporum and Cylindrocarpon lucidum, is an immunosuppressant prescribed in organ transplants to prevent rejection. Its adverse effect on renal dysfunction has limited its use in a clinical setting. Apigenin (4',5',7'-Trihydroxyflavone), a herbal extract, with anti-inflammatory and anti-tumour properties, has been investigated for properties to reverse this adverse effect. This research was conducted to establish a standard protocol for immunohistochemical estimation of Transforming Growth Factor beta (TGF-beta) expression, as an indicator of Cyclosporine A induced damage, and to observe whether apoptotic index and TGF-beta expression can be used to assess effects of Apigenin on CsA induced renal dysfunction. Six groups of 5 male Sprague-Dawley albino rats each were dosed once daily for 21 days, as follows: (1) negative control--oral corn oil, (2) positive control--Cyclosporine A (25 mg/kg), (3) Group 3--Apigenin (20 mg/kg), (4) Group 4--Cyclosporine A (25 mg/kg) +Apigenin (10 mg/kg), (5) Group 5--Cyclosporine A (25 mg/kg) +Apigenin (15 mg/kg) and (6) Group 6--Cyclosporine A (25 mg/kg) +Apigenin (20 mg/kg). Cyclosporine A was administered intra-peritoneally while Apigenin was given orally. The rat kidneys were harvested and examined microscopically to assess the apoptotic index, and stained by immunohistochemistry for multifunctioning polypeptide TGF-beta expression. A high apoptotic index and TGF-beta intensity was observed in the Cyclosporine A group. Apigenin significantly reduced the both apoptotic index and TGF-beta intensity. The apoptotic index correlated with TGF-beta intensity, especially in glomeruli. This study indicates that Cyclosporine A can enhance the TGF-beta expression in rat kidney, signifying accelerated apoptosis. TGF-beta and apoptotic index may be used to assess Apigenin and its effect on Cyclosporine A induced renal damage.
Ethanol intoxication resulted in high extent of lipid peroxidation, and reduction in antioxidant defenses (decreased GSH, GSH/GSSG ratio, and catalase, SOD and GPx activities) and (Na+/K+)-ATPase activity in kidney. Alpha-tocopherol treatment effectively protected kidney from ethanol induced oxidative challenge and improved renal (Na+/K+)-ATPase activity. Ethanol induced oxidative stress in the kidney and decreased (Na+/K+)-ATPase activity could be reversed by treatment with ascorbic acid.
Labisia pumila (Myrsinaceae), is a popular herb among the women in Malaysia known locally as "Kacip Fatimah". Recently many nutraceutical products containing the powdered or extracted parts of the plant have become available for women's health care. However no evaluation of the effect of the repeated dosing of any herbal product of this plant had been undertaken prior to a 28-day sub-acute study presented in this report. The results showed that a dose of 50mg/kg of an aqueous extract of L. pumila corresponded to no-adverse-effect-level (NOAEL), whereas higher doses were associated with some toxicity concerns.