Low oxygen microenvironment and cardiovascular remodeling: Role of dual L/N.type Ca2+ channel blocker.

OBJECTIVE: Patients exposed to chronic sustained hypoxia frequently develop cardiovascular disease risk factors to ultimately succumb to adverse cardiovascular events. In this context, the present study intends to assess the role of cilnidipine (Cil), a unique calcium channel blocker that blocks both L-type and N-type calcium channels, on cardiovascular pathophysiology in face of chronic sustained hypoxia exposure. MATERIALS AND METHODS: The study involved Wistar strain albino rats. The group-wise allocation of the experimental animals is as follows - Group 1, control (21% O2); Group 2, chronic hypoxia (CH) (10% O2, 90% N); Group 3, Cil + 21% O2; and Group 4, CH (10% O2, 90% N) + Cil (CH + Cil). Cardiovascular hemodynamics, heart rate variability, and endothelial functions (serum nitric oxide [NO], serum endothelial nitric oxide synthase [NOS3], and serum vascular endothelial growth factor [VEGF]) were assessed. Cardiovascular remodeling was studied by histopathological examination of the ventricular tissues, coronary artery (intramyocardial), and elastic and muscular arteries. Normalized wall index of the coronary artery was also calculated. RESULTS AND CONCLUSION: The results demonstrated altered cardiovascular hemodynamics, disturbed cardiovascular autonomic balance, increased levels of VEGF and NOS3, and decreased bioavailability of NO on exposure to chronic sustained hypoxia. The histopathological examination further pointed toward cardiovascular remodeling. Treatment with Cil ameliorated the cardiovascular remodeling and endothelial dysfunction induced by CH exposure, which may be due to its blocking actions on L/N-type of calcium channels, indicating the possible therapeutic role of Cil against CH-induced cardiovascular pathophysiology.

Effect of L-Ascorbic Acid on Nickel-Induced Alteration of Cardiovascular Pathophysiology in Wistar Rats.

Nickel, a widely used heavy metal is suspected as a cardiotoxic element. The aim of the present study was to assess the possible protective role of l-ascorbic acid on nickel-induced alterations of cardiovascular pathophysiology in male albino rats. Twenty-four albino rats (b.wt. 170-250 g) were randomized into four groups: control; l-ascorbic acid (50 mg/100 g b.wt., orally); NiSO4 (2.0 mg/100 g b.wt., i.p.); NiSO4 with l-ascorbic acid. Cardiovascular electrophysiology, serum and cardiac tissue malondialdehyde (MDA), nitric oxide (NO), ascorbic acid, serum α-tocopherol and serum vascular endothelial growth factor (VEGF) were evaluated. Histopathology of cardiac and aortic tissues was also assessed. NiSO4-treated rats showed a significant increase in heart rate, LF/HF ratio and blood pressure (SBP, DBP and MAP). A significant increase of serum MDA, NO and VEGF in NiSO4 treatment with a concomitant decrease of serum ascorbic acid and α-tocopherol as compared to their respective controls were also observed. Simultaneous supplementation of l-ascorbic acid with NiSO4 significantly decreased LF/HF ratio, BP and oxidative stress parameters, whereas ascorbic acid and α-tocopherol concentration was found to be increased. Histopathology of cardiac and aortic tissues showed nickel-induced focal myocardial hypertrophy and degeneration in cardiac tissue with focal aneurism in aortic tissues. Supplementation with l-ascorbic showed a protective action in both cardiac and aortic tissues. Results indicated the possible beneficial effect of l-ascorbic acid on nickel-induced alteration of the cardiovascular pathophysiology in experimental rats.

Subchronic hypoxia pretreatment on brain pathophysiology in unilateral common carotid artery occluded albino rats.

OBJECTIVE: This study was aimed to assess the effect of unilateral common carotid artery occlusion on brain pathophysiology in rats pretreated with subchronic hypoxia. MATERIALS AND METHODS: Rats (200 ± 20 g) were randomized into three groups: Group 1 served as sham, Group 2 were normoxic (21% O2 and 79% N2), and Group 3 were hypoxia preconditioned (10% O2 and 90% N2) for 21 days before left common carotid artery occlusion (LCCAO). The LCCAO was done for 75 min followed by reperfusion for 12 h. Neurological scores were recorded. Serum malondialdehyde (MDA) and nitric oxide (NO) levels at pre- and 12 h post-LCCAO were measured. Brain histopathological assessments were also done. RESULTS: Higher neurological deficits scores in Group 2 as compared to Group 3 rats were noticed. Serum MDA and NO levels at 12 h post-LCCAO in Group 2 rats showed significant elevation as compared to preocclusion levels. Group 3 rats did not show such elevations. On histopathology of left and right cerebral hemispheres of Group 1 (sham) did not show any specific changes. In Group 2 rats, the right cerebral hemisphere (nonoccluded) showed no areas of ischemia-induced brain changes, but in the left side (occlusive), there were features of ischemic brain damage including cerebral edema. In the case of Group 3 rats, there were less ischemic damages in the left occluded side as compared to the left side of the Group 2 rats. CONCLUSION: This study clearly demonstrates that subchronic hypoxia pretreatment can reduce ischemic brain injury by unilateral common carotid artery occlusion in rats.

Sub-chronic indomethacin treatment and its effect on the male reproductive system of albino rats: possible protective role of black tea extract.

BACKGROUND: Indomethacin is commonly used as a nonsteroidal anti-inflammatory drug (NSAID) to treat inflammation, arthritis and joint pains. Unfortunately, it has a wide range of adverse effects on the physiological system, including gonads. This study aimed to assess possible beneficial effects of black tea extract (BTE) against indomethacin-induced alteration of gonadal hormone levels in male rats. METHODS: Adult male rats were divided into Group I (control), Group II (indomethacin, 5 mg/kg body weight [bwt.]; i.p., 21 days), Group III (BTE, 2.5 g tea leaf/dL of water, i.e. 2.5% of aqueous BTE, orally, 21 days) and Group IV (indomethacin+BTE, 21 days). Sperm count and motility, serum luteinising hormone (LH), follicle-stimulating hormone (FSH) and testosterone, along with histopathology of testes were studied. One-way ANOVA, followed by post-hoc t-test were conducted. RESULTS: Indomethacin-treated rats showed significant decrease in testicular weight, sperm count, sperm motility, serum gonadotropins and testosterone concentrations. Histopathology of the testes showed tortuous and distorted seminiferous tubules, marked thickening of the tubular basement membrane, reduced spermatogenesis process (>30%) and marked decrease in the number of interstitial cells of Leydig in indomethacin-treated rats. Interestingly, rats supplemented with BTE showed remarkable improvements in testicular weight gain, sperm count and motility, serum gonadotropins and testosterone concentrations, along with testicular histopathology. CONCLUSIONS: The results suggest that BTE might have potential ameliorative effects against sub-chronic indomethacin-induced alteration of gonadal hormone levels in male albino rats.

Dose Dependent Hepatic and Endothelial Changes in Rats Treated with Dexamethasone.

AIMS AND OBJECTIVES: To study the effect of dexamethasone on liver and endothelium, and to determine the optimum dose which induces the abnormal changes in liver and endothelium in Wistar rats. MATERIALS AND METHODS: Albino Wistar rats were divided into 7 groups (n=6). Control group rats received normal saline. Graded doses of dexamethasone (0.5,1,2,4,8 and 16mg/kg/ i.p.) was administered to the groups for six days. Liver and aorta were dissected at the end of the study and examined for histopathological changes under microscope. RESULTS: Intraperitoneal administration of dexamethasone (4,8 and 16mg/kg) for six days resulted in fatty changes in liver and same doses have shown thickening of endothelial layers in aorta, in comparison to control group. There were not much significant changes seen in low doses of dexamethasone (0.5, 1 and 2mg/kg). CONCLUSION: It is concluded that the acute high doses of dexamethasone (4,8 and 16mg/kg) for six days caused hepatic steatosis and showed mild to moderate arteriosclerosis in aorta. These changes may be secondary consequences of insulin resistance. Hence, it can be used as new animal model to screen the various plants and medicines in the treatment of insulin resistance.

α-tocopherol supplementation prevents lead acetate and hypoxia-induced hepatic dysfunction.

OBJECTIVE: Lead (Pb) is a long-known poison of environment and industrial origin. Its prolonged exposure affects cellular material and alters cellular genetics and produces oxidative damages. In this study, we investigated the exposure of chronic sustained hypoxia or lead acetate alone or in combination with or without supplementation of α-tocopherol on hepatic oxidative and nitrosative stress in rats. MATERIALS AND METHODS: The rats weighing 165 ± 5 g were exposed to chronic sustained hypoxia (10% oxygen) or lead acetate (25 mg/kg of body weight, intraperitoneally) alone or in combination with or without supplementation of α-tocopherol (10 mg/100 g b.wt, intramuscularly). The body weight of all the rats was recorded on the day 1 of the treatment and the day of sacrifice. Serum lipid profile was estimated by using a biochemical analyzer. Oxidant and enzymatic antioxidants status was evaluated by using spectrophotometer. Serum levels of hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by using ELISA technique. Histopathological assessments of hepatic tissue were also done. RESULTS: Exposure of both lead and hypoxia showed decreased body weight, altered serum lipid profile, oxidant and enzymatic antioxidants status, serum HIF-1α and VEGF concentrations. Simultaneous α-tocopherol supplementation showed beneficial effects to all these alterations. Histopathological observations also showed hepatic degenerative changes after lead or hypoxia exposure either alone or in combination, but remarkable improvement has been noticed after α-tocopherol supplementation. CONCLUSION: Supplementation of α-tocopherol is beneficial to counter both lead acetate and hypoxia induced hepatic cytotoxicities possibly by reducing oxidative and nitrosative stress.

Protective effect of L-ascorbic acid on nickel induced pulmonary nitrosative stress in male albino rats.

Nickel sulfate stimulates inducible nitric oxide synthase (i-NOS) and increases serum nitric oxide concentration by overproduction of reactive nitrogen species due to nitrosative stress. The present study was undertaken to assess possible protective role of L-ascorbic acid as an antioxidant against nickel induced pulmonary nitrosative stress in male albino rats. We studied the effect of the simultaneous treatment with L-ascorbic acid (50 mg/100 g b. wt.; orally) and nickel sulfate (2.0 mg/100 g b. wt.; i.p.) on nitric oxide synthesis by quantitative evaluation of serum i-NOS activities, serum and lung nitric oxide, L-ascorbic acid and protein concentrations of Wistar strain male albino rats. We have further studied histopathological changes in lung tissue after nickel sulfate treatment along with simultaneous exposure of L-ascorbic acid. Nickel sulfate treatment significantly increased the serum i-NOS activity, serum and pulmonary nitric oxide concentration and decreased body weight, pulmonary somatic index, serum and lung L-ascorbic acid and protein concentration as compared to their respective controls. Histopathological changes induced by nickel sulfate showed loss of normal alveolar architecture, inflammation of bronchioles, infiltration of inflammatory cells and patchy congestion of alveolar blood vessels. The simultaneous administration of L-ascorbic acid and nickel sulfate significantly improved all the above biochemical parameters along with histopathology of lung tissues of rats receiving nickel sulfate alone. The study clearly showed a protective role of L-ascorbic acid against nickel induced nitrosative stress in lung tissues.

α-Tocopherol ameliorates nickel induced testicular oxidative and nitrosative stress in albino rats.

BACKGROUND: Heavy metals generate free radicals and induce oxidative and nitrosative stress with depletion of antioxidants. In this study, we have evaluated the beneficial effects of α-tocopherol against nickel sulfate exposed testicular dysfunction. METHODS: We studied the effect of supplementation of α-tocopherol (10 mg/100 g body weight, i.m.) on nickel sulfate (2.0 mg/100 g body weight, i.p.) induced testicular oxidative and nitrosative stress in Wister strain male albino rats. Serum and testicular nitric oxide, L-ascorbic acid and serum α-tocopherol concentrations were evaluated. We also evaluated sperm count, motility and histopathology of testes. RESULTS: Nickel treated rats showed significantly decreased body weight, testicular somatic index, sperm count, sperm motility, serum and testicular L-ascorbic acid concentration and serum α-tocopherol level as compared to their controls. However, simultaneous treatment with nickel sulfate and α-tocopherol produced a remarkable improvement of all the above parameters when compared with treatment with nickel alone. Nickel treated rats also had significantly increased serum and testicular nitric oxide concentrations as compared to their controls. However, simultaneous treatment with nickel sulfate and α-tocopherol significantly decreased nitric oxide concentrations in both serum and testes, respectively, as compared to nickel treatment alone. Histopathology of the testes revealed tortuous seminiferous tubules, loss of spermatogenesis process (>75%), congestion and necrosis in nickel sulfate treated rats, whereas rats simultaneously treated with nickel sulfate and α-tocopherol had almost normal seminiferous tubules and near normal spermatogenesis as compared to nickel alone treated rats. CONCLUSIONS: Nickel sulfate treatment causes testicular oxidative and nitrosative stress in albino rats, but simultaneous supplementation of α-tocopherol was found to be beneficial in combating against such stresses.