Cyclosporine A-induced alterations in magnesium homeostasis in the rat

The immunosuppressive drug cyclosporine A (CsA) exhibits significant nephrotoxicity. Disturbance of magnesium (Mg) homeostasis may be an important component of this nephrotoxicity. It has been suggested that transmigration of Mg from plasma to tissues may be an important component of CsA-induced alterations in Mg homeostasis. In this study, CsA nephrotoxicity in male Wistar rats was investigated and alterations in Mg homeostasis along with other indices of toxicity were assessed. Animals were dosed daily for 14 days i.p. with CsA (20 mg/kg body weight). Control animals received vehicle alone. CsA toxicity was evidenced by i) lower gain in body weight, ii) reduced thymus/body weight ratio, iii) increased blood urea nitrogen and creatinine, iv) a tendency for reduced plasma magnesium and v) increased urinary Mg excretion and greatly increased fractional excretion of Mg. Tissue Mg analysis did not reveal any changes in thymus or skeletal muscle Mg while Mg in kidney tissue tended to be reduced. Electron microscopy revealed some damage in renal tubules of rats treated with cyclosporine including translucent cytoplasm, vacuolization, rounded and swollen mitochondria, damage to brush border and disruption of basal infoldings. These results indicate that direct renal tubular damage may result from CsA exposure. No evidence was found for CsA-induced movement of Mg from plasma to tissues. CsA-induced altered renal handling of Mg and this renal Mg wasting may be an important consequence of the nephrotoxicity.     

The time-dependent effect of Provinols on brain NO synthase activity in L-NAME-induced hypertension

Red wine polyphenols have been reported to possess beneficial properties for preventing cardiovascular diseases but their neuroprotective effects during chronic L-NAME treatment have not been elucidated. The aim of this study was to analyze a time course of Provinols effects on brain NO synthase activity and oxidative damage in L-NAME-induced hypertension. Male Wistar rats, 12 weeks old, were divided into six groups: control groups, groups treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg/day) for 4 or 7 weeks and groups receiving Provinols (40 mg/kg/day) plus L-NAME for 4 or 7 weeks. At the end of the treatment, marker of membrane oxidative damage - conjugated dienes (CD) in the brain and NO synthase activity in the cerebral cortex, cerebellum and brainstem were determined. L-NAME treatment for 4 or 7 weeks led to the increase in blood pressure, elevation of CD concentration and decrease of NO synthase activity in the brain parts investigated. Provinols partially prevented blood pressure rise and elevation of CD concentration. Comparing to the L-NAME treated group, Provinols increased NO synthase activity after 4 weeks of treatment. However, the prolonged Provinols treatment for 7 weeks had no effect on NO synthase activity decreased by L-NAME treatment. In conclusion, Provinols partially prevents L-NAME induced hypertension via the different mechanisms depending on the duration of treatment. Prevention of oxidative damage in the brain with modulating effect on NO synthase activity is suggested.     

Vascular changes in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.

Functional and morphological changes of blood vessels in cyclosporine A (CsA)-induced hypertension and nephrotoxicity were studied in spontaneously hypertensive rats (SHR). The role of the L-arginine-nitric oxide (NO) pathway and the importance of oxidative stress in CsA toxicity were also assessed. SHR (7-8 week old) on a high-sodium diet were treated with CsA (5 mg kg(-1) d(-1) s.c.) for 6 weeks. A proportion of the rats were treated concomitantly with the NO precursor L-arginine (1.7 g kg(-1)d(-1) p.o.). CsA elevated blood pressure and caused renal dysfunction and morphological nephrotoxicity. CsA also impaired mesenteric and renal arterial function and caused structural damage to intrarenal and extrarenal small arteries and arterioles. Medial atrophy of the mesenteric resistance vessels and decreased viability of smooth muscle cells of the thoracic aorta were observed. Renal and arterial damage was associated with the presence of inflammatory cells. CsA did not affect markers of the L-arginine-NO pathway (urinary cyclic GMP excretion or endothelial or inducible NO synthase expression in kidney, aorta or heart) or oxidative stress (urinary excretion of 8-isoprostaglandin F2alpha, plasma urate concentration or total radical trapping capacity). Concomitant L-arginine treatment did not affect CsA-induced changes in blood pressure or histological findings but tended to alleviate the arterial dysfunction. The renal and cardiovascular toxicity of CsA was associated with arterial dysfunction and morphological changes in small arteries and arterioles in SHR on a high-sodium diet. The findings did not support the role of oxidative stress or a defect in the L-arginine-NO pathway.     

Vascular effects of red wine polyphenols in chronic stress-exposed Wistar-Kyoto rats

Present study investigated the effect of red wine polyphenolic compounds (Provinols) on blood pressure (BP), nitric oxide synthase (NOS) activity and vascular function in Wistar-Kyoto (WKY) rats exposed to chronic social stress produced by crowding. Adult male rats were divided into four groups: control (480 cm(2)/rat), Provinols-treated (20 mg/kg/day, 480 cm(2)/rat), crowded (200 cm(2)/rat) and crowded treated with Provinols (20 mg/kg/day, 200 cm(2)/rat) for 8 weeks. No differences in BP were observed among the groups at the end of experiment, however, reduced BP was observed in Provinols-treated rats after 3 weeks of treatment. NOS activity in the aorta was significantly elevated in crowded rats, while Provinols alone had no effect on nitric oxide (NO) production. Acetylcholine-induced relaxation of the femoral artery was significantly improved in stressed and Provinols-treated rats vs. control, without significant changes in their noradrenaline-induced vasoconstriction. Interestingly, Provinols blunted the elevation of NO production and vasorelaxation during crowding. Increased endothelium-dependent vasorelaxation and NO synthesis in crowded rats may represent the adaptation mechanisms, resulting in unaltered blood pressure in stress-exposed normotensive rats. This study further demonstrated that elevated release of NO during chronic stress may be prevented by Provinols. Thus, Provinols might maintain equilibrium between endothelium-derived vasoconstrictor and vasodilator factors in stress.     

Effect of calcium treatment on blood parameters,gonadal development and the structure of bone in immature female rats

Calcium is an essential nutrient required for critical biological functions. Calcium supplementation is to be evaluated using immature female rats. The present study focused on some blood parameters, gonadal development and bone structure. Forty immature female Sprague–Dawley rats were randomly divided into four equal-sized groups (80 g average body weight) to receive calcium chloride dihydrate (group I: control; groups II, III and IV: received 20 mg, 40 mg and 60 mg per kg body weight, respectively) for 5 weeks. Rats were decapitated, and their trunk blood was sampled for biochemical assays. Cholesterol, triglycerides, glucose and calcium were measured. Gonadal and bone structure were histologically evaluated. Results revealed that treatment of developing female rats with three calcium doses used have no marked effect on the serum calcium and cholesterol levels. However, serum triglyceride level and body weight gain are significantly decreased in rats treated with all of the three calcium doses. Serum glucose level showed a marked increase in animals treated with the higher calcium doses. Moreover, observable histological alterations are recognized in the ovaries. Bones of the experimental animals also showed morphological alterations. These results suggest that increasing calcium supplementation decreases triglycerides and percentage body weight gain and positively affects the bone and gonadal development.     

Veratric acid ameliorates hyperlipidemia and oxidative stress in Wistar rats fed an atherogenic diet

An investigation was made to reveal the protective effects of veratric acid (VA), a phenolic acid against atherogenic diet-induced hyperlipidemic rats. Male albino Wistar rats were fed with atherogenic diet (4% cholesterol, 1% cholic acid, and 0.5% 2-thiouracil) daily for 30 days and treated with VA (40 mg/kg body weight) daily for a period of 30 days. Rats fed with atherogenic diet showed significant (P < 0.05) elevation in the level of plasma lipids, systolic and diastolic blood pressure, oxidative stress markers (thiobarbituric acid reactive substances, lipid peroxides) and significant (P < 0.05) reduction in the activities of enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic (vitamin C, vitamin E, and reduced glutathione) antioxidants in erythrocytes, plasma, and tissues (liver, kidney, and aorta). Oral administration of VA (40 mg/kg body weight) for 30 days to atherogenic diet fed rats markedly attenuates systolic, diastolic blood pressure and lipid peroxidation products. Further, VA treatment significantly improved enzymatic and non-enzymatic antioxidants levels and showed beneficial effects on lipid profile in atherogenic diet rats. All the above alterations were supported by histopathological observations. These results indicate that oral administration of VA ameliorates atherogenic diet-induced hyperlipidemia in rats by its free radical scavenging; improving the antioxidants and lipid lowering properties.     

Beneficial effects of Provinols: cardiovascular system and kidney

Red wine polyphenols have been reported to exert beneficial effects in preventing cardiovascular diseases but their molecular mechanisms of hemodynamic effects on functional cardiovascular and renal changes were studied much less. The review is focused on in vitro as well as in vivo effects of red wine extract containing polyphenolic compounds (Provinols) on cardiovascular systems and kidney in relation to the molecular and biochemical mechanisms of these compounds. This review provides the evidence that Provinols is able to produce ex vivo endothelium-dependent relaxation as a result of enhanced NO synthesis. Administration of Provinols partially prevents the development of hypertension during NO deficiency and accelerates the decrease of blood pressure in already established hypertension. The effects of Provinols include prevention and/or attenuation of myocardial fibrosis, reduction of aortic wall thickening and improvement of vascular functions. These functional and structural alterations are associated with significant augmentation of NO production, seen as the increase of NO synthase activity and eNOS protein expression. Moreover, it has been documented that Provinols decreased the oxidative stress within the cardiovascular system and kidney.     

A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats

Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg.kg(-1).day(-1)) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P < 0.05) lowered plasma levels of triglycerides, total cholesterol, and LDL-cholesterol. HDL-cholesterol concentrations were significantly higher (P < 0.05) in the flaxseed oil-treated group compared with the other two groups. Both flaxseed oil and fish oil may provide similar biochemical, hemodynamic, and inflammatory benefits after heart transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model.     

Nephrotoxicity of cyclosporin A in hereditary hypertriglyceridemic rats

It has been suggested that cyclosporin A (CsA) nephrotoxicity can be reduced by the concomitant administration of omega-3 fatty acids or vitamin E. The present study was designed to establish whether the effect of the above substances can also be demonstrated in rats with hereditary hypertriglyceridemia (HTG) whose sensitivity to the nephrotoxic effect is greater than in control AVN rats. CsA administration at a dose of 10 mg/kg/day to HTG rats resulted in a significant rise (p<0.001) in serum levels of creatinine (from 66.0+/-7.6 to 108.4+/-11.6 micromol/l) and urea (from 8.3+/-0.7 to 22.3+/-18 mmol/l) which was not found in AVN rats. The baseline values of systolic blood pressure (SBP) were significantly higher in HTG rats. However, in both strains CsA administration was associated with a similar SBP increase which was not prevented by omega-3 fatty acids (EPAX) or vitamin E administration. Concomitant administration of CsA with EPAX at a dose of 600 mg/kg b.w./day in HTG rats prevented the rise in the serum levels of creatinine (65.4+/-14.7 micromol/l) and reduced the increase in the serum urea levels (11.9+/-7.6 mmol/l). Concomitant administration of CsA and vitamin E (at a dose of 25 mg/kg/day) also reduced the increase (p<0.05) in the serum levels of creatinine (70.7+/-14.3 micromol/l) and urea (9.8+/-3.4 mmol/l) compared to the effects elicited by the administration of CsA alone (p<0.05). Administration of CsA alone or in combination with EPAX or vitamin E did not have a marked effect on diuresis, proteinuria, urinary osmolality, urinary excretion of urea, creatinine and potassium. Under all experimental conditions, the rate of urinary excretion of sodium in HTG rats was significantly lower (p<0.01) than in AVN rats. The results obtained support the assumption that omega-3 fatty acids and vitamin E at the doses used reduce CsA nephrotoxicity in rats with hereditary hypertriglyceridemia whose sensitivity to the nephrotoxic effect of CsA is significantly higher than in AVN rats.     

Effects of phosphates on the expression of tissue-nonspecific alkaline phosphatase gene and phosphate-regulating genes in short-term cultures of human osteosarcoma cell lines

Cyclosporine A (CsA) has been universally used as an immunosuppressant for the management of organ transplantation and various autoimmune diseases. However, nephrotoxicity due to CsA remains to be an important clinical challenge. In the present investigation, an attempt has been made to appraise the effect of sulphated polysaccharides on oxidative renal injury caused by CsA. Adult male Wistar rats were divided into four groups. Two groups received CsA by oral gavage (25 mg/kg body weight) for 21 days to provoke nephrotoxicity, one of which simultaneously received sulphated polysaccharides subcutaneously, (5 mg/kg body weight). A vehicle (olive oil) treated control group and sulphated polysaccharides drug control were also built-in. An increase in lipid peroxidation along with abnormal levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase) and non-enzymic antioxidants (glutathione, vitamin C and vitamin E) are the salient features observed in CsA induced nephrotoxicity. CsA induced impairment of renal toxicity was evident from the marked decline in the activities of renal marker enzymes like alkaline phosphatase, acid phosphatase and lactate dehydrogenase, as well as an apparent increase in the serum urea, uric acid and creatinine; diagnostic of renal damage was normalized by sulphated polysaccharides co-administration. Sulphated polysaccharides treatment showed an effectual role in counteracting the free radical toxicity by bringing about a significant decrease in peroxidative levels and increase in antioxidant status. These observations emphasize the antioxidant property of sulphated polysaccharides and its cytoprotective action against CsA induced nephrotoxicity.     

Change in renal heme oxygenase expression in cyclosporine A-induced injury.

Cyclosporine A (CsA) is the first immunosuppressant used in allotransplantation. Its use is associated with side effects that include nephrotoxicity. This study explored the anatomic structures involved in CsA nephrotoxicity and the effect of heme oxygenase (HO) in preventing CsA injury. Rats were divided into four groups, which were treated with olive oil, CsA (15 mg/kg/day), CsA plus the HO inhibitor (SnMP; 30 microM/kg/day), and with the HO inducer (CoPP; 5 mg/100 g bw). Renal tissue was treated for morphological, biochemical, and immunohistochemical studies. CsA-treated rats showed degenerative changes with renal fibrosis localized mainly around proximal tubules. Collapsed vessels were sometimes seen in glomeruli. No HO-1 expression and increased expression of endothelin-1 (ET-1) were observed in CsA-treated rats compared with controls. In CsA plus SnMP-treated rats, HO-1 expression was further reduced and the morphology was not changed compared to the CsA group, whereas CsA plus CoPP-treated animals again showed normal morphology and with restoration and an increase in HO-1 levels. HO activity and immunohistochemical data showed similar alterations as HO expression. No changes were observed for HO-2 analysis. The observations indicate that HO-1 downregulation and ET-1 upregulation by CsA might be one mechanism underlying CsA-induced nephrotoxicity. Therefore, attempts to preserve HO levels attenuate CsA nephrotoxicity.     

Grape polyphenols and exercise training have distinct molecular effects on cardiac hypertrophy in a model of obese insulin-resistant rats

Obesity and exercise lead to structural changes in heart such as cardiac hypertrophy. The underlying signaling pathways vary according to the source of the overload, be it physiological (exercise) or pathologic (obesity). The physiological pathway relies more on PI3K-Akt signaling while the pathologic pathway involves calcineurin-Nuclear factor of activated T-cells activation and fibrosis accumulation. Independently, exercise and polyphenols have demonstrated to prevent pathologic cardiac hypertrophy. Therefore, we investigated the molecular adaptations of the combination of exercise training and grape polyphenols supplementation (EXOPP) in obese high-fat fed rats on heart adaptation in comparison to exercise (EXO), polyphenols supplementation (PP) and high-fat fed rats (HF), alone. Exercised and PP rats presented a higher heart weight/body weight ratio compared to HF rats. EXO and EXOPP depicted an increase in cell-surface area, P-Akt/Akt, P-AMPK/AMPK ratios with a decreased fibrosis and calcineurin expression, illustrating an activation of the physiological pathway, but no additional benefit of the combination. In contrast, neither cell-surface area nor Akt signaling increased in PP rats; but markedly decreased fibrosis, calcineurin expression, systolic blood pressure, higher SERCA and P-Phospholamdan/Phospholamdan levels were observed. These data suggest that PP rats have a shift from pathologic toward physiological hypertrophy. Our study demonstrates that polyphenols supplementation has physical-activity-status-specific effects; it appears to be more protective in sedentary obese insulin-resistant rats than in the exercised ones. Exercise training improved metabolic and cardiac alterations without a synergistic effect of polyphenols supplementation. These data highlight a greater effect of exercise than polyphenols supplementation for the treatment of cardiac alterations in obese insulin-resistant rats.     

Effect of pentoxifylline on cyclosporine-induced nephrotoxicity in rats

Effect of unique hemorrheologic agent pentoxifylline (PTX) was investigated on cyclosporine (CsA) induced nephrotoxicity in rats. Compared to saline control, CsA produced significant increase in blood urea and serum creatinine. Pentoxifylline treatment prevented the CsA-induced rise in blood urea and serum creatinine. Creatinine clearance (Ccr) and lithium clearance (Licr) was decreased with CsA. PTX treatment prevented the CsA-induced decrease in Ccr and Licr. Malondialdehyde (MDA) was increased with CsA compared to saline treated animals. PTX prevented the CsA-induced MDA rise. Kidney form CsA treated rat showed marked vacuolar degeneration of tubular epithelium with excess of microcalcification. Severity of the lesions was markedly reduced in rats treated with PTX plus CsA. The results indicate that PTX reduces CsA-induced renal toxicity in rats.     

Effects of chronic insulin treatment on blood pressure in rats

There is an evident epidemiological association between plasma insulin levels and blood pressure. The mechanism that relates insulin to blood pressure and the role of insulin in the pathogenesis of arterial hypertension have not been clearly defined. The present study was designed to examine the effects of chronic hyperinsulinism on blood pressure and to determine different related morphological variables. WistarKyoto rats were subcutaneously injected with insulin (25 UI/Kg of weight) daily during the eight weeks of the experiment. Data were collected on systolic and diastolic arterial pressures and heart rate by plethysmography and direct recording (in the last week), and on morphological variables. A statistically significant elevation of systolic arterial pressure was produced after the sixth week of hyperinsulinaemia. At the end of the treatment, the systolic arterial pressure was 173.7 +/- 26.1 in the hyperinsulinaemic rats versus 153.09 +/- 21.7 in the control group. The values obtained by direct recording and by plethysmography did not differ. These results indicate that chronic hyperinsulinism produces a significant elevation in systolic blood pressure levels in the rats studied.     

Provinol prevents CsA-induced nephrotoxicity by reducing reactive oxygen species, iNOS, and NF-kB expression.

Cyclosporine A (CsA) use is associated with several side effects, the most important of which is nephrotoxicity that includes, as we previously showed, tubular injury and interstitial fibrosis. Recently, many researchers have been interested in minimizing these effects by pharmacological interventions. To do this, we tested whether the administration of a red wine polyphenol, Provinol (PV), prevents the development of CsA-induced nephrotoxicity. Rats were treated for 21 days and divided into four groups: control; group treated with PV (40 mg/kg/day by oral administration in tap water); group treated with CsA (15 mg/kg/day by subcutaneous injection); group treated with CsA plus PV. CsA produced a significant increase of systolic blood pressure; it did not affect urinary output, but caused a significant decrease in creatinine clearance. These side effects were associated with an increase in conjugated dienes, which are lipid peroxidation products, inducible NO-synthase (iNOS), and nuclear factor (NF)-kB, which are involved in antioxidant damage. However, PV prevented these negative effects through a protective mechanism that involved reduction of both oxidative stress and increased iNOS and NF-kB expression induced by CsA. These results provide a pharmacological basis for the beneficial effects of plant-derived polyphenols against CsA-induced renal damage associated with CsA.     

Celecoxib prevents pressure overload‐induced cardiac hypertrophy and dysfunction by inhibiting inflammation,apoptosis and oxidative stress

To explore the effects of celecoxib on pressure overload‐induced cardiac hypertrophy (CH), cardiac dysfunction and explore the possible protective mechanisms. We surgically created abdominal aortic constrictions (AAC) in rats to induce CH. Rats with CH symptoms at 4 weeks after surgery were treated with celecoxib [2 mg/100 g body‐weight(BW)] daily for either 2 or 4 weeks. Survival rate, blood pressure and cardiac function were evaluated after celecoxib treatment. Animals were killed, and cardiac tissue was examined for morphological changes, cardiomyocyte apoptosis, fibrosis, inflammation and oxidative stress. Four weeks after AAC, rats had significantly higher systolic, diastolic and mean blood pressure, greater heart weight and enlarged cardiomyocytes, which were associated with cardiac dysfunction. Thus, the CH model was successfully established. Two weeks later, animals had impaired cardiac function and histopathological abnormalities including enlarged cardiomyocytes and cardiac fibrosis, which were exacerbated 2 weeks later. However, these pathological changes were remarkably prevented by the treatment of celecoxib, independent of preventing hypertension. Mechanistic studies revealed that celecoxib‐induced cardiac protection against CH and cardiac dysfunction was due to inhibition of apoptosis via the murine double mimute 2/P53 pathway, inhibition of inflammation via the AKT/mTOR/NF‐κB pathway and inhibition of oxidative stress via increases in nuclear factor E2‐related factor‐2‐mediated gene expression of multiple antioxidants. Celecoxib suppresses pressure overload‐induced CH by reducing apoptosis, inflammation and oxidative stress.     

Effects of decylubiquinone (coenzyme Q10 analog) supplementation on SHRSP

Decylubiquinone treatment in vitro has demonstrated a potent inhibitor effect on reactive oxidative species production. However, the effectin vivo has not been demonstrated yet. Thus, rats SHRSP male were divided in two groups: treated and controls (n=6, each). The treated group received 10 mg/Kg(-)/body weight of decylubiquinone diluted in coconut oil by oral gavage during four weeks. Control rats just received the vehicle. Body weight, diuresis, food and water intake, systolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood glucose levels and malondialdehyde were determined. There were a significant (p<0.05) reduction on systolic blood pressure, plasma malondialdehyde, total cholesterol and LDL-cholesterol in the treated group. Additionally, HDL-cholesterol also increased significantly. However, body weight, diuresis, food and water intake, blood glucose levels and triglycerides did not alter after treatment. Thus, decylubiquinone can be a new antihypertensive, hypolipidemic and antioxidant agent on the prevention and treatment of diseases linked to oxidative stress.     

Cyclosporine A dosing-time-dependent effects on plasma creatinine and body weight in male Wistar rats treated for 3 weeks.

Cyclosporine A (CsA) nephrotoxicity was assessed in 120 male Wistar rats (350 +/- 50 g) entrained to a 12-h cycle (light-dark 12:12); plasma creatinine level and body weight were examined in controls and in rats that had been treated daily with oral CsA or vehicle alone (olive oil-ethanol 90:10) for 21 days; daily dosing (40 mg/kg) was at one of six equally spaced given times during the 24-h cycle. The variations observed in both indexes were shown to be circadian dosing stage dependent. Nephrotoxicity was present as early as the third day of treatment with CsA; plasma creatinine level was enhanced by about 50% in rats dosed around the time of the change from darkness to light: at 22 HALO, 146.7 +/- 4.5 mumol/L, against 92.0 +/- 2.8 mumol/L for controls (p less than 0.05); and at 2 HALO, 148.3 +/- 10.0 mumol/L, against 95.0 +/- 4.3 mumol/L for controls (p less than 0.05). Thereafter, a remission episode was observed between days D5-D9. The more drastic effects were seen on days D16 and D21, in animals dosed in the beginning of the dark span (14 HALO): 185 +/- 10 mumol/L for CsA and 98.0 +/- 5.3 mumol/L for controls (p less than 0.01) and, to a lesser extent, in rats treated at the early resting phase (2 HALO): 152.4 +/- 31 mumol/L for CsA and 95.0 +/- 4 mumol/L for controls (p less than 0.05). The normal increase in body weight during the 21-day period (about 14 +/- 8% in controls) was impeded in CsA-administered rats, especially those dosed at the beginning of the activity span (14 HALO) that even suffered weight reduction. Differences in percentages of survivors were noticed, depending on dosing stage. About 40% of the animals in every time CsA-treatment group died, except for those dosed at the end of the resting period (10 HALO), when all animals died. In surviving rats, the cessation of CsA dosing resulted in a reversible effect on the study variables.     

Agiotensin II induced cardiac hypertrophy in vivo is inhibited by cyclosporin A in adult rats

Recently, the calciumcalmodulindependent calcineurin pathway has been defined as a central pathway for the induction of cardiac hypertrophy. The purpose of this study was to determine if cardiac hypertrophy in animals chronically treated with angiotensin II (AngII), could be prevented by blocking this pathway with cyclosporin A (CsA). Female Wistar rats were treated with AngII by subcutaneous infusion and injected twice a day with CsA (25 mg/kg) for 7 days. In the AngII treated group there was a 30% increase in the heart/body weight ratio (p < 0.05 vs. control). The increase in heart weight was blocked with CsA. Substantial increases in ANF and MHC gene expression were detected in the AngII treated animals, which were either attenuated or blocked with CsA treatment. Thus, this study demonstrates that CsA does prevent the development of cardiac hypertrophy in Ang II treated rats, suggesting that the calciumcalmodulindependent calcineurin pathway is associated with angiotensin II induced hypertrophy in vivo.     

Protection of glomerular filtration rate by the thromboxane receptor antagonist L655,240 during low dose cyclosporine administration

Cyclosporin A (CsA) alters the production of prostaglandins (PG) by the kidney. CsA causes an increase in renal vascular resistance, a decrease in renal blood flow, a decrease in glomerular filtration rate (GFR), and increases the renal production of the vasoconstrictor thromboxane. Recently, low dose CsA has been utilized in the treatment of refractory autoimmune diseases. To determine if low dose CsA administration could produce renal hemodynamic alterations and to determine if the thromboxane receptor antagonist L655,240 could prevent these alterations, we administered groups of rats either CsA, 5 mg/kg, subcutaneously and the L655,240 vehicle NaHCO₃ (CsA-NaHCO₃), or CsA and L655,240 (CsA-L655,240), or CsA vehicle and L655,240. The rats were administered the drugs for 7 days and then subjected to inulin and PAH clearances or kidneys were harvested for prostaglandin production studies. CsA significantly depressed GFR and renal plasma flow when compared to the L655,240 treated groups. There was no difference in inulin or PAH clearance between the CsA-L655,240 and CsA vehicle L655,240 groups. Glomerular prostaglandin production including thromboxane was depressed by CsA administration. No histologic alterations were noted in the glomeruli or the medullary portions of the kidney. We conclude that administration of low dose CsA, 5 mg/kg, for 7 days results in a decrease in renal blood flow and GFR without histologic alterations. Administration of the thromboxane receptor antagonist L655,240 prevents the renal hemodynamic alterations induced by CsA in this rat model.