Hypertension induced by immunosuppressive drugs: a comparative analysis between sirolimus and cyclosporine.

The purpose of this study was to compare the effects of sirolimus (SRL) vs cyclosporine (CsA) concerning the cardiovascular mechanisms hypothetically contributing to hypertension development. Three rat groups were studied: control (vehicle), CsA (5 mg/kg/d), and SRL (1 mg/kg/d). The following parameters were evaluated after 7 weeks of treatment: blood pressured (BP) and heart rate (HR; tail cuff), lipid profile, hematology, plasma and platelet 5-HT and catecholamines (HPLC-ECD), and oxidative equilibrium (serum malondialdehyde [MDA] and total antioxidant status [TAS]). Systolic (SBP) and diastolic blood pressure (DBP) values were higher (P < .001) in both the CsA (146.2 +/- 4.5 and 124.9 +/- 4.5 mm Hg) and SRL (148.9 +/- 4.8 and 126.4 +/- 6.0 mm Hg) groups vs the controls (115.9 +/- 3.3 and 99.1 +/- 2.0 mm Hg). However, HR values were elevated in CsA but not SRL animals. The dyslipidemic pattern of CsA was even more enhanced in the SRL group, with significantly higher low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels vs CsA (P < .05); red blood cells, hematocrit, hemoglobin concentration, mean platelet volume, and platelet distribution width were significantly (P < .05) higher in the SRL vs CsA group. The pro-oxidative profile (increased MDA/TAS) in the CsA group was not reproduced in the SRL cohort. While plasma and platelet 5-HT were elevated in SRL rats, catecholamine content was higher in CsA animals. In conclusion, this study demonstrated that CsA and SRL produce identical hypertensive effects. However, while CsA promotes oxidative stress and sympathetic activation, SRL mainly interferes with lipid profile and hematological parameters. Thus, the hypertensive effects of CsA, a calcineurin inhibitor, and of SRL, an mTOR inhibitor, are associated with impairment of distinct cardiovascular pathways.

Exercise training decreases proinflammatory profile in Zucker diabetic (type 2) fatty rats.

OBJECTIVE: In the present study we evaluated the effect of exercise on the plasma levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory molecule uric acid in the Zucker diabetic fatty (ZDF) rats that are more prone to develop type 2 diabetes mellitus. METHODS: Sixteen obese ZDF (Gmi fa/fa) rats (8 wk old, 228.40 +/- 4.05 g) were randomly assigned to one of two groups (n = 8 each): an exercise-trained group and a sedentary one. In addition, 16 lean ZDF (Gmi +/+) rats (8 wk old, 199.00 +/- 3.50 g) were subjected to identical sedentary and exercise conditioning (n = 8 each). Initially, rats swam 15 min/d (5 d/wk) in a 36 degrees C bath. The exercise protocol was gradually increased by 15 min/d until a swimming period of 1 h/d (1 wk) was attained. Thereafter, rats swam 1 h/d, 3 d/wk, for an additional period of 11 wk. Rats were sacrificed 48 h after the last training period and the blood and pancreas were collected. Circulating levels of glucose, glycosylated hemoglobin, total cholesterol, triglycerides, insulin, uric acid, IL-6, and TNF-alpha were assessed. The concentrations of proinflammatory cytokines in the pancreas were also evaluated. RESULTS: In the diabetic ZDF (fa/fa) rats, exercise decreased hyperuricemia (-37.3%) and IL-6 and TNF-alpha levels (-16.9% and -12.7% respectively) and maintained the weight of the pancreas at near normal. Immunohistochemistry revealed a marked decrease in the expression of TNF-alpha and IL-6 in the pancreatic islet cells of ZDF (fa/fa) rats. CONCLUSION: These results indicate that aerobic exercise is anti-inflammatory in nature.

Treadmill running and swimming imposes distinct cardiovascular physiological adaptations in the rat: focus on serotonergic and sympathetic nervous systems modulation.

Physical exercise may improve the metabolic and haemodynamic responses, but the beneficial effects seem to depend on intensity, duration and muscular mass recruitment, which may vary between different types of protocols. This study was performed to evaluate the effects of two distinct moderate/long-term aerobic training protocols in the normal Wistar rat, the treadmill running and the swimming, on several important parameters related to cardiovascular (CV) physiological adaptations, namely: lipid profile, haemorheological measures, lipid peroxidation, peripheral serotonergic system (SS) modulation and sympathetic nervous system (SNS) activation. In both groups under training an HDL-c increment versus the sedentary control was demonstrated. There was a noticeable increase in ADP-induced platelet aggregation in the exercised rats, together with higher PDW and MPV values. The RBC patterns were altered in both groups under training; in the swimming one, however, significantly higher RBC and HCT and lower MCH and MCHC values were found, suggesting renovation of the RBCs. Plasma and platelet SS measures were generally higher in both groups under training, being noticeably relevant the 5-HT and 5-HIAA increment in the treadmill. In opposition, concerning the plasma and platelet NE and E concentrations, the rise was remarkably higher in the rats under a swimming protocol. In conclusion, this study demonstrates that, despite the similar beneficial effects on lipid profile, different aerobic exercise protocols may produce distinct CV physiological adaptations. Therefore, treadmill running was more influent than swimming concerning peripheral SS modulation while swimming was more important on SNS activation, thus recommending a judicious choice of the protocol to be tested in works which make use of rat models of exercise to study physiological or pathophysiological conditions.

Oxidative stress in cyclosporine-induced hypertension: evidence of beneficial effects or tolerance development with nitrate therapy.

The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n = 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn + CsA therapy showed, when compared with the CsA group, total prevention of CsA-induced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA + Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 +/- 1.4 vs 12.78 +/- 3.63 mumol/L; P < .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.

Dual effect of nitrate therapy for cyclosporine-induced hypertension on vascular and platelet morphofunctional markers; an animal model.

The present study sought to evaluate the prevention and reversion effects of isosorbide-5-mononitrate (Is-5-Mn) on the development of hypertension (HT) and on the underlying vascular and platelet morphofunctional disturbances, using an animal model of cyclosporine (CsA)-induced HT. The following rat groups (n = 8) were tested: (1) a control group (orange juice, for 7 weeks); (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the prevention group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA and following thereafter with both drugs for 5 weeks. Blood pressure, lipid profile, vascular lesion, platelet aggregation and morphology, and platelet thromboxane A(2)/vascular prostacyclin equilibrium were evaluated. Is-5-Mn + CsA therapy prevented (systolic blood pressure [SBP]: 114.3 +/- 1.9 mm Hg, P < .001; diastolic blood pressure [DBP]: 97.0 +/- 3.3 mm Hg, P < .001) the CsA-induced HT (SBP: 146.2 +/- 4.5 mm Hg, P < .001; DBP: 124.9 +/- 4.5 mm Hg, P < .001 vs control: SBP: 111.6 +/- 0.7 mm Hg; DBP: 94.6 +/- 1.0 mm Hg), as well as the vascular lesion and the platelet morphofunctional disturbances. The curative group did not show attenuated CsA-induced BP increase; it showed further enhancement of the HT effect (SBP: 159.7 +/- 5.5 mm Hg, P < .05; DBP: 132.8 +/- 2.8 mm Hg), as well as worsened vascular lesions and platelet function, namely a disruption in the TXA(2)/PGI(2) equilibrium. Our data suggested that Is-5-Mn therapy may be a valid choice to prevent the morphofunctional changes associated with CsA-induced HT, when used as a preventive therapy. A careful evaluation of the impact of nitrate therapy should be considered, particularly the negative effect on cardiovascular hemodynamics, when considering its use after previous CsA disturbances have been established.