Munavvar Abdul Sattar

Our main objective was to investigate the effect of chronic administration of hydrogen sulphide donor (sodium hydrosulphide) on the expression of intercellular adhesion molecule-1 (ICAM-1) and concentration of nuclear factor-kappa B (NF-kB) in a renal ischemia-reperfusion injury (IRI) model of WKY and L-nitro-arginine-methyl-ester (L-NAME)-induced hypertensive rats. Sodium hydrosulphide (NaHS) was administered intraperitoneally (i.p.) for 35 days while cystathionine gamma lyase (CSE) inhibitor dL-propargylglycine (PAG) was administered at a single dose of 50 mg/kg. Animals were anesthetised using sodium pentobarbitone (60 mg/kg) and then prepared to induce renal ischemia by clamping the left renal artery for 30 min followed by 3 h of reperfusion. Pre-treatment with NaHS improved the renal functional parameters in both WKY and L-NAME-induced hypertensive rats along with reduction of blood pressure in hypertensive groups. Oxidative stress markers like malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione (GSH) were also improved by NaHS treatment following renal IRI. Levels of ICAM-1 and NF-kB concentration were reduced by chronic treatment with NaHS and increased by PAG administration after renal IRI in plasma and kidney. Treatment with NaHS improved tubular morphology and glomerulus hypertrophy. Pre-treatment with NaHS reduced the degree of renal IRI by potentiating its antioxidant and anti-inflammatory mechanism, as evidenced by decreased NF-kB concentration and downregulation of ICAM-1 expression.

Oxidative stress, which is associated with metabolic and anthropometric perturbations, leads to reactive oxygen species production and decrease in plasma adiponectin concentration. We investigated pharmacodynamically the pathophysiological role and potential implication of exogenously administered adiponectin with full and partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists on modulation of oxidative stress, metabolic dysregulation, and antioxidant potential in streptozotocin-induced spontaneously hypertensive rats (SHR). Group I (WKY) serves as the normotensive control, whereas 42 male SHRs were randomized equally into 7 groups ( ); group II serves as the SHR control, group III serves as the SHR diabetic control, and groups IV, V, and VI are treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg), and adiponectin (2.5 μg/kg), whereas groups VII and VIII received cotreatments as irbesartan+adiponectin and pioglitazone+adiponectin, respectively. Diabetes was induced using an intraperitoneal injection of streptozotocin (40 mg/kg). Plasma adiponectin, lipid contents, and arterial stiffness with oxidative stress biomarkers were measured using an in vitro and in vivo analysis. Diabetic SHRs exhibited hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and increased arterial stiffness with reduced plasma adiponectin and antioxidant enzymatic levels ( ). Diabetic SHRs pretreated with pioglitazone and adiponectin separately exerted improvements in antioxidant enzyme activities, abrogated arterial stiffness, and offset the increased production of reactive oxygen species and dyslipidemic effects of STZ, whereas the blood pressure values were significantly reduced in the irbesartan-treated groups (all ). The combined treatment of exogenously administered adiponectin with full PPAR-γ agonist augmented the improvement in lipid contents and adiponectin concentration and restored arterial stiffness with antioxidant potential effects, indicating the degree of synergism between adiponectin and full PPAR-γ agonists (pioglitazone).

Background Oxidative stress, associates with metabolic and anthropometric perturbations, leads to reactive oxygen species production and decrease in plasma adiponectin concentration. We investigated pharmacodynamically the pathophysiological role and potential implication of exogenously administered adiponectin with full and partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists on modulation of oxidative stress, metabolic dysregulation and antioxidant potential in streptozotocin induced Spontaneously hypertensive rats (SHR).Methods Group I (WKY) serve as normotensive control, whereas 42 male SHRs were randomized equally into 7 groups (n = 6), group II: SHR control, groups III: SHR diabetic control, group IV, V and VI treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg) and adiponectin (2.5 µg/kg), whereas, groups VII and VIII received co-treatments as irbesartan + adiponectin), (pioglitazone + adiponectin) respectively. Diabetes was induced using an intra-peritoneal injection of Streptozotocin (40 mg/kg). Plasma adiponectin, lipid contents, arterial stiffness with oxidative stress bio-markers were measured using an in-vitro and in-vivo analysis.Results Diabetic SHRs exhibited hyperglycaemia, hypertriglyceridemia, hypercholesterolemia, increased arterial stiffness with reduced plasma adiponectin and antioxidant enzymatic levels (P < 0.05). Diabetic SHRs pre-treated with pioglitazone and adiponectin separately exerted improvements in antioxidant enzyme activities, abrogated arterial stiffness, offset the increased production of reactive oxygen species and dyslipidaemic effects of STZ, except for blood pressure values which were more pronounced with irbesartan treated groups (all P < 0.05).Conclusions The combined treatment of exogenously administered adiponectin with full PPAR-γ agonist augmented the improvement in lipid contents and adiponectin concentration, restores arterial stiffness with antioxidant potential effects, indicating degree of synergism between adiponectin and full PPAR-γ agonists (pioglitazone).

Pioglitazone, a therapeutic drug for diabetes, possesses full PPAR-γ agonist activity and increase circulating adiponectin plasma concentration. Plasma adiponectin concentration decreases in hypertensive patients with renal dysfunctions. Present study investigated the reno-protective, altered excretory functions and renal haemodynamic responses to adrenergic agonists and ANG II following separate and combined therapy with pioglitazone in diabetic model of hypertensive rats. Pioglitazone was given orally [10mg/kg/day] for 28 days and adiponectin intraperitoneally [2.5µg/kg/day] for last 7 days. Groups of SHR received either pioglitazone or adiponectin in combination. A group of Wistar Kyoto rats [WKY] served as normotensive controls, whereas streptozotocin administered SHRs served as diabetic hypertensive rats. Metabolic data and plasma samples were taken on day 0, 8, 21 and 28. In acute studies, the renal vasoconstrictor actions of Angiotensin II [ANGII], noradrenaline [NA], phenylephrine [PE] and methoxamine [ME] were determined. Diabetic SHRs control had a higher basal mean arterial blood pressure than the WKY, lower RCBP and plasma adiponectin, higher creatinine clearance and urinary sodium excretion compared to WKY [all P<0.05] which were normalized by the individual drug treatments and to greater degree following combined treatment. Responses to intra-renal administration of NA, PE, ME and ANGII were larger in diabetic SHR than WKY and SHRs [P<0.05]. Adiponectin significantly blunted responses to NA, PE, ME and ANG II in diabetic treated SHRs by 40%, whereas the pioglitazone combined therapy with adiponectin further attenuated the responses to adrenergic agonists by 65%. [all P <0.05]. These findings suggest that adiponectin possesses renoprotective effects and improves renal haemodynamics through adiponectin receptors and PPAR-γ in diabetic SHRs, suggesting that synergism exists between adiponectin and pioglitazone. A cross-talk relationship also supposed to exists between adiponectin receptors, PPAR-γ and alpha adrenoceptors in renal vasculature of diabetic SHRs.

The purpose of the present study was to investigate the interaction between H₂S and NO (nitric oxide) in the kidney and to evaluate its impact on the functional contribution of α_1A and α_1B-adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy (LVH). In rats the LVH induction was by isoprenaline administration and caffeine in the drinking water together with intraperitoneal administration of H₂S. The responsiveness of α_1A and α_1B to exogenous noradrenaline, phenylephrine and methoxaminein the absence and presence of 5-methylurapidil (5-MeU) and chloroethylclonidine (CEC) was studied. Cystathione gamma lyase (CSE), cystathione β synthase (CBS), 3-mercaptopyruvate sulphar transferase (3-MST) and endothelial nitric oxide synthase (eNOS) were quantified. There was significant up regulation of CSE and eNOS in the LVH-H₂S compared to the LVH group (P2S compared to the LVH group. The responsiveness of α_1A-adrenergic receptors to adrenergic agonists was increased (P2S group while α_1B-adrenergic receptors responsiveness to adrenergic agonists were increased (P2S group. Treatment of LVH with H₂S resulted in up-regulation of CSE/H₂S, CBS, and 3-MST and eNOS/NO/cGMP pathways in the kidney. These up regulation of CSE/H₂S, CBS, and 3-MST and eNOS/NO/cGMP pathways enhanced the responsiveness of α_1A and α_1B-adrenoreceptors subtypes to adrenergic agonists in LVH-H₂S. These findings indicate an important role for H₂S in modulating deranged signalling in the renal vasculature resulting from LVH development.

Hydrogen sulphide (H₂S) is an emerging molecule in many cardiovascular complications but its role in left ventricular hypertrophy (LVH) is unknown. The present study explored the effect of exogenous H₂S administration in the regression of LVH by modulating oxidative stress, arterial stiffness and expression of cystathione γ lyase (CSE) in the myocardium. Animals were divided into four groups: Control, LVH, Control-H₂S and LVH-H₂S. LVH was induced by administering isoprenaline (5mg/kg, every 72 hours, S/C) and caffeine in drinking water (62mg/L) for 2 weeks. Intraperitoneal NaHS, 56μM/kg/day for 5 weeks, was given as an H₂S donor. Myocardial expression of Cystathione γ lyase (CSE) mRNA was quantified using real time polymerase chain reaction (qPCR).There was a 3 fold reduction in the expression of myocardial CSE mRNA in LVH but it was up regulated by 7 and 4 fold in the Control-H₂S and LVH-H₂S myocardium, respectively. Systolic blood pressure, mean arterial pressure, pulse wave velocity were reduced (all P2S when compared to the LVH group. Heart, LV weight, myocardial thickness were reduced while LV internal diameter was increased (all P2S when compared to the LVH group. Exogenous administration of H₂S in LVH increased superoxide dismutase, glutathione and total antioxidant capacity but significantly reduced (all P2S compared to the LVH group. The renal cortical blood perfusion increased by 40% in LVH-H₂S as compared to the LVH group. Exogenous administration of H₂S suppressed the progression of LVH which was associated with an up regulation of myocardial CSE mRNA/ H₂S and a reduction in pulse wave velocity with a blunting of systemic hemodynamic. This CSE/H₂S pathway exhibits an antihypertrophic role by antagonizing the hypertrophic actions of angiotensin II(Ang II) and noradrenaline (NA) but attenuates oxidative stress and improves pulse wave velocity which helps to suppress LVH. Exogenous administration of H₂S augmented the reduced renal cortical blood perfusion in the LVH state.

The present study investigated the role of endothelial nitric oxide synthase (eNOS) enzyme in the development of left ventricular hypertrophy (LVH) in Wistar-Kyoto rats. The effect of L-arginine administration on cardiac structure, arterial stiffness, renal and systemic hemodynamic parameters was studied and the change in expression of eNOS and cystathione γ lyase (CSE) in the myocardium of LVH rats was evaluated. LVH was induced using isoprenaline (5 mg/kg, S.C.) and caffeine (62 mg/L in drinking water) for 14 days. Following to that, L-arginine (1.25 g/L in drinking water) was given for 5 weeks as a donor of NO. eNOS and CSE gene expressions were down regulated in the LVH group by about 35% and 67% respectively when compared to control. However, in the LVH group treated with L-arginine there was up regulation of eNOS by almost 27% and down regulation in CSE by 24% when compared to control (all P < 0.05). Heart index and H2S plasma levels were reduced by almost 53% in the L-arginine treated LVH group compared to the control (all P < 0.05). Mean arterial pressure, heart rate and pulse wave velocity were reduced while renal blood perfusion increased in L-arginine treated LVH rats compared to their untreated counterparts (all P < 0.05). The enhanced expression of eNOS in L-arginine treated LVH rats resulted in the amelioration of oxidative and haemodynamic parameters suggesting that NO system is an important therapeutic target in cardiac and LV hypertrophies.

Left ventricular hypertrophy (LVH) is a compensatory mechanism in response to an increased work load on the heart. This study investigated the impact of chronic isoprenaline and caffeine (I/C model) administration on cardiac geometry, systemic hemodynamic and physiological data in rats as LVH develops. LVH was induced by administering isoprenaline (5 mg/kg s.c. every 72 h) and caffeine (62 mg/L) in drinking water for 14 days to Wistar Kyoto (WKY) rats. Mean arterial pressure (MAP), systolic blood pressure (SBP), heart weight, LV weight, LV chamber diameter and thickness of myocardium were observed as LVH indicators. MAP was significantly higher (142 +/- 13 vs. 119 +/- 2 mmHg, respectively) while heart rate (HR) in LVH was lower (314 +/- 9 vs. 264 +/- 18 BPM) compared to control WKY. Heart weight, LV weight and kidney weight were 31%, 38% and 7%, respectively, greater in the LVH group as compared to the control WKY (all p < 0.05).The myocardium thickness was 101% greater while LV chamber diameter was 44% smaller in the LVH group as compared to the control WKY (p < 0.05). The superoxide dismutase (SOD), glutathione reductase (GSH) and total antioxidant capacity (T-AOC) levels were significantly reduced while malonodialdehyde (MDA) level increased in LVH as compared to control WKY (all p < 0.05). In conclusion, isoprenaline and caffeine (I/C) induces LVH and cardiac hypertrophy with increases in blood pressure, fluid excretion and reduced renal hemodynamics. Prooxidant mechanism of the body and arterial stiffness are dominant in this disease model. This model of LVH is easily generated and associated with low mortality.