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Effect of pioglitazone on vasopressor responses to adrenergic agonists and angiotensin II in diabetic and non-diabetic spontaneously hypertensive rats

Afzal S, Sattar MA, Akhtar S, Binti Abdullah NA, Eseyin OA, Abdulla MH, et al.

Pak J Pharm Sci, 2018 May;31(3):747-754.
PMID: 29716851

Pioglitazone, peroxisome proliferator-activated receptor (PPAR-γ) agonist, is a therapeutic drug for diabetes. Present study investigated the interaction between PPAR-γ and alpha adrenoceptors in modulating vasopressor responses to Angiotensin II (Ang II) and adrenergic agonists, in diabetic & non-diabetic Spontaneously Hypertensive Rats (SHRs). Diabetes was induced with an i.p injection of streptozotocin (40 mg/kg) in two groups (STZ-CON, STZ-PIO), whereas two groups remained non diabetic (ND-CO, ND-PIO). One diabetic and non-diabetic group received Pioglitazone (10mg/kg) orally for 21 days. On day 28, the animals were anaesthetized with sodium pentobarbitone (60mg/kg) and prepared for measurement of systemic haemodynamics. Basal mean arterial pressure of STZ-CON was higher than ND-CON, whereas following pioglitazone treatment, MAP was lower compared to respective controls. MAP responses to i.v administration of NA, PE, ME and ANG II were significantly lower in diabetic SHRs: STZ-CON vs ND-CON (35%). Pioglitazone significantly decreased responses to NA, PE, ME and ANG II in ND-PIO versus ND-CON by 63%. Responses to NA and ANG II were significantly attenuated in STZ-PIO vs. ND-PIO (40%). PPAR-γ regulates systemic hemodynamic in diabetic model and cross-talk relationship exists between PPAR-γ and α1-adrenoceptors, ANG II in systemic vasculature of SHRs.
Fulltext Antioxidant Potential of Adiponectin and Full PPAR-γ Agonist in Correcting Streptozotocin-Induced Vascular Abnormality in Spontaneously Hypertensive Rats

Afzal S, Sattar MA, Johns EJ, Eseyin OA, Attiq A

PPAR Res, 2021;2021:6661181.
PMID: 34691163 DOI: 10.1155/2021/6661181

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 (n = 6); 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 (P < 0.05). 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 P < 0.05). 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).
Renal sympathetic nervous system hyperactivity in early streptozotocin-induced diabetic kidney disease

Salman IM, Ameer OZ, Sattar MA, Abdullah NA, Yam MF, Abdullah GZ, et al.

Neurourol Urodyn, 2011 Mar;30(3):438-46.
PMID: 21284025 DOI: 10.1002/nau.21007

We assessed the role of renal sympathetic nervous system in the deterioration of renal hemodynamic and excretory functions in rats with streptozotocin (STZ)-induced diabetic kidney disease (DKD).
Clonidine and a novel clonidine analog AL-12 cause sympathoinhibition in spontaneously hypertensive and diabetic spontaneously hypertensive rats

Lazahari MI, Sattar MA, Abdullah NA, Khan MA, Johns EJ

Methods Find Exp Clin Pharmacol, 2008 Apr;30(3):193-9.
PMID: 18597003 DOI: 10.1358/mf.2008.30.3.1166221

This study examined the sympathoinhibitory effects of clonidine and a novel clonidine analog, AL-12, in rat models of genetic hypertension and a combined state of genetic hypertension and diabetes. Rats in the treatment groups were given either clonidine or AL-12 while the respective control groups received either saline or Tween 80 for 6 days. Physiological data were collected during this period, which was followed by acute studies on day 7 when bolus administrations (i.v.) of graded doses of noradrenaline, phenylephrine and methoxamine were carried out. It was observed that in AL-12-treated nondiabetic spontaneously hypertensive rats (SHR), the pressure responses to all adrenergic agonists were greater (p < 0.05) in the treated group, while in the diabetic SHR rats a larger pressure response was observed only to noradrenaline (p < 0.05). In nondiabetic SHR rats treated with clonidine, a greater (p < 0.05) pressure response was observed only in the case of phenylephrine. In the diabetic SHR rats treated with clonidine, the pressure responses to the adrenergic agonists were similar (p > 0.05) in the treated and its control animals except that methoxamine caused a greater (p < 0.05) pressure response in the control group. The data obtained suggest that clonidine and AL-12 act possibly via vascular alpha1 and alpha2 adrenoceptors present at both pre- and postsynaptic locations.
Functional subtypes of renal alpha1-adrenoceptor in spontaneously hypertensive rats with streptozotocin-induced experimental diabetic nephropathy

Khan MA, Sattar MA, Abdullah NA, Abdulla MH, Salman IM, Kazi RN, et al.

Kidney Blood Press Res, 2009;32(5):349-59.
PMID: 19844130 DOI: 10.1159/000249149

This study investigated the impact of hypertension combined with diabetic nephropathy on rat renal alpha(1)-adrenoceptor subtype composition.
Enhanced expression of endothelial nitric oxide synthase in the myocardium ameliorates the progression of left ventricular hypertrophy in L-arginine treated Wistar-Kyoto rats

Ahmad A, Sattar MA, Rathore HA, Abdulla MH, Khan SA, Abdullah NA, et al.

J. Physiol. Pharmacol., 2016 Feb;67(1):31-44.
PMID: 27010893

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 (1.25g/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.
Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats

Afzal S, Sattar MA, Johns EJ, Abdulla MH, Akhtar S, Hashmi F, et al.

J Physiol Biochem, 2016 Dec;72(4):593-604.
PMID: 27405250

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P
The effect of losartan and carvedilol on renal haemodynamics and altered metabolism in fructose-fed Sprague-Dawley rats

Abdulla MH, Sattar MA, Abdullah NA, Johns EJ

J Physiol Biochem, 2012 Sep;68(3):353-63.
PMID: 22281695 DOI: 10.1007/s13105-012-0147-1

The aim of this study is to assess the effects of losartan and carvedilol on metabolic parameters and renal haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of fructose-fed rat. Thirty-six Sprague-Dawley rats were fed for 8 weeks either 20% fructose solution (F) or tap water (C) ad libitum. F or C group received either losartan or carvedilol (10 mg/kg p.o.) daily for the last 3 weeks of the study (FL and L) and (FCV and CV), respectively, then in acute studies the renal vasoconstrictor actions of Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. Data, mean±SEM were analysed using ANOVA with significance at P <0.05. Losartan and carvedilol decreased the area under the glucose tolerance curve of the fructose-fed group. The responses (%) to NA, PE, ME and Ang II in F were lower (P <0.05) than C (F vs. C, 17±2 vs. 38±3; 24±2 vs. 48±2; 12±2 vs. 34±2; 17±2 vs. 26±2), respectively. L had higher (P <0.05) responses to NA and PE while CV had blunted (P <0.05) responses to NA, PE and Ang II compared to C (L, CV vs. C, 47±3, 9±2 vs. 38±3; 61±3, 29±3 vs. 48±2; 16±3, 4±3 vs. 26±2), respectively. FL but not FCV group had enhanced (P <0.05) responses to NA, PE and ME compared to F (FL vs. F, 33±3 vs. 17±2; 45±3 vs. 24±2; 26±3 vs. 12±2), respectively. Losartan and carvedilol had an important ameliorating effect on fructose-induced insulin resistance. Losartan treatment could be an effective tool to restore normal vascular reactivity in the renal circulation of the fructose-fed rat.
Role of renal sympathetic nervous system in the control of renal potassium handling

Salman IM, Sattar MA, Abdullah NA, Ameer OZ, Basri F, Hussain NM, et al.

J Nephrol, 2010 May-Jun;23(3):291-6.
PMID: 20349424

It is well established that renal sympathetic nerves are primarily involved in renal sodium and water regulation. However, the relationship between renal sympathetic nerve activity (RSNA) and renal potassium handling is not extensively known. The present study was performed to investigate the role of the renal sympathetic nervous system in the regulation of tubular potassium reabsorption and secretion.
Characterization of renal hemodynamic and structural alterations in rat models of renal impairment: role of renal sympathoexcitation

Salman IM, Ameer OZ, Sattar MA, Abdullah NA, Yam MF, Najim HS, et al.

J Nephrol, 2010 5 4;24(1):68-77.
PMID: 20437405 DOI: 10.5301/jn.2010.6

BACKGROUND: Renal sympathetic innervation plays an important role in the control of renal hemodynamics and may therefore contribute to the pathophysiology of many disease states affecting the kidney. Thus, the present study aimed to investigate the role of the renal sympathetic nervous system in the early deteriorations of renal hemodynamics and structure in rats with pathophysiological states of renal impairment.

METHODS: Anesthetized Sprague Dawley (SD) rats with cisplatin-induced acute renal failure (ARF) or streptozotocin (STZ)-induced diabetes mellitus (DM) were subjected to a renal hemodynamic study 7 days after cisplatin and STZ administration. During the acute study, renal nerves were electrically stimulated, and responses in renal blood flow (RBF) and renal vascular resistance (RVR) were recorded in the presence and absence of renal denervation. Post mortem kidney collection was performed for histopathological assessment.

RESULTS: In innervated ARF or DM rats, renal nerve stimulation produced significantly lower (all p<0.05, vs. innervated control) renal vasoconstrictor responses. These responses were markedly abolished when renal denervation was performed (all p<0.05); however, they appeared significantly higher compared with denervated controls (all p<0.05). Kidney injury was suppressed in denervated ARF, while, irrespective of renal denervation, renal specimens from DM rats were comparable to controls.

CONCLUSIONS: Renal sympathoexcitation is involved in the pathogenesis of the renal impairment accompanying ARF and DM, and may even precede the establishment of an observable renal injury. There is a possible enhancement in the renal sensitivity to intrarenal norepinephrine following renal denervation in ARF and DM rats.
Fulltext Exposure to High-Fat Style Diet Induced Renal and Liver Structural Changes, Lipid Accumulation and Inflammation in Intact and Ovariectomized Female Rats

Sucedaram Y, Johns EJ, Husain R, Abdul Sattar M, H Abdulla M, Nelli G, et al.

J Inflamm Res, 2021;14:689-710.
PMID: 33716510 DOI: 10.2147/JIR.S299083

Purpose: We hypothesized that low estrogen levels aggravate obesity-related complications. Diet-induced obesity can cause distinct pathologies, including impaired glucose tolerance, inflammation, and organ injury that leads to fatty liver and chronic kidney diseases. To test this hypothesis, ovariectomized (OVX) rats were fed a high-fat style diet (HFSD), and we examined structural changes and inflammatory response in the kidney and liver.
Methods: Sprague-Dawley female rats were ovariectomized or sham-operated and divided into four groups: sham-operated rats fed a normal diet (ND); ovariectomized rats fed a normal diet (OVX-ND); sham-operated rats fed a HFSD; ovariectomized rats fed a high-fat style diet (OVX-HFSD). Mean blood pressure and fasting blood glucose were measured on weeks 0 and 10. The rats were sacrificed 10 weeks after initiation of ND or HFSD, the kidney and liver were harvested for histological, immunohistochemical and immunofluorescence studies.
Results: HFSD-fed rats presented a significantly greater adiposity index compared to their ND counterparts. Liver index, fasting blood glucose and mean blood pressure was increased in OVX-HFSD rats compared to HFSD rats at study terminal. Histological and morphometric studies showed focal interstitial mononuclear cell infiltration in the kidney of HFSD rats with mesangial expansion being greater in the OVX-HFSD rats. Both HFSD fed groups showed increased expressions of renal inflammatory markers, namely TNF-alpha, IL-6 and MCP-1, and infiltrating M1 macrophages with some influence of ovarian hormonal status. HFSD-feeding also caused hepatocellular steatosis which was aggravated in ovariectomized rats fed the same diet. Furthermore, hepatocellular ballooning was observed only in the OVX-HFSD rats. Similarly, HFSD-fed rats showed increased expressions of the inflammatory markers and M1 macrophage infiltration in the liver; however, only IL-6 expression was magnified in the OVX-HFSD.
Conclusion: Our data suggest that some of the structural changes and inflammatory response in the kidney and liver of rats fed a HFSD are exacerbated by ovariectomy.
Renal Nano-drug delivery for acute kidney Injury: Current status and future perspectives

Geo HN, Murugan DD, Chik Z, Norazit A, Foo YY, Leo BF, et al.

J Control Release, 2022 Jan 24;343:237-254.
PMID: 35085695 DOI: 10.1016/j.jconrel.2022.01.033

Acute kidney injury (AKI) causes considerable morbidity and mortality, particularly in the case of post-cardiac infarction or kidney transplantation; however, the site-specific accumulation of small molecule reno-protective agents for AKI has often proved ineffective due to dynamic fluid and solute excretion and non-selectivity, which impedes therapeutic efficacy. This article reviews the current status and future trajectories of renal nanomedicine research for AKI management from pharmacological and clinical perspectives, with a particular focus on appraising nanosized drug carrier (NDC) use for the delivery of reno-protective agents of different pharmacological classes and the effectiveness of NDCs in improving renal tissue targeting selectivity and efficacy of said agents. This review reveals the critical shift in the role of the small molecule reno-protective agents in AKI pharmacotherapy - from prophylaxis to treatment - when using NDCs for delivery to the kidney. We also highlight the need to identify the accumulation sites of NDCs carrying reno-protective agents in renal tissues during in vivo assessments and detail the less-explored pharmacological classes of reno-protective agents whose efficacies may be improved via NDC-based delivery. We conclude the paper by outlining the challenges and future perspectives of NDC-based reno-protective agent delivery for better clinical management of AKI.
Acute renal failure in 2K2C Goldblatt hypertensive rats during antihypertensive therapy: comparison of an angiotensin AT1 receptor antagonist and clonidine analogues

Sattar MA, Yusof AP, Gan EK, Sam TW, Johns EJ

J Auton Pharmacol, 2001 5 15;20(5-6):297-304.
PMID: 11350495

1. This study compared the effect of a non-peptide angiotensin II receptor antagonist and a series of clonidine analogues on blood pressure and renal function in a two-kidney two-clip Goldblatt rat model of hypertension subjected to 2 weeks of dietary sodium deprivation. 2. Animals received either vehicle, the angiotensin II antagonist, ZD7155 or structural analogues derived from clonidine (AL-11, AL-12 and CN-10) at 10 mg kg-1 day-1 for 4 days. 3. All groups of rats had systolic blood pressure in the hypertensive range (160-180 mmHg). ZD7155 caused a 33-mmHg fall in blood pressure (P < 0.05) and raised plasma urea and creatinine four- to six-fold. 4. AL-12 decreased blood pressure by 30 mmHg (P < 0.05), but had no effect on water intake, urine flow or plasma urea and creatinine. AL-11 and CN-10 had minimal effects on blood pressure and water intake and while CN-10 decreased urine flow on the third treatment day, AL-11 markedly reduced urine flow by some 70%. 5. These data show that in this sodium deficient renovascular model of hypertension, blockade of angiotensin II receptors normalizes blood pressure but causes renal failure, whereas the vasodepressor action of the clonidine analogue AL-12 occurs without detriment to renal function. These findings imply that angiotensin II receptor antagonists could lead to renal failure if used as antihypertensive agents in renovascular hypertension whereas this would be avoided with the use of clonidine-like analogues.
Fulltext The Relation between Fructose-Induced Metabolic Syndrome and Altered Renal Haemodynamic and Excretory Function in the Rat

Abdulla MH, Sattar MA, Johns EJ

Int J Nephrol, 2011;2011:934659.
PMID: 21785727 DOI: 10.4061/2011/934659

This paper explores the possible relationships between dietary fructose and altered neurohumoral regulation of renal haemodynamic and excretory function in this model of metabolic syndrome. Fructose consumption induces hyperinsulinemia, hypertriglyceridaemia, insulin resistance, and hypertension. The pathogenesis of fructose-induced hypertension is dubious and involves numerous pathways acting both singly and together. In addition, hyperinsulinemia and hypertension contribute significantly to progressive renal disease in fructose-fed rats. Moreover, increased activity of the renin-angiotensin and sympathetic nervous systems leading to downregulation of receptors may be responsible for the blunted vascular sensitivity to angiotensin II and catecholamines, respectively. Various approaches have been suggested to prevent the development of fructose-induced hypertension and/or metabolic alteration. In this paper, we address the role played by the renin-angiotensin and sympathetic nervous systems in the haemodynamic alterations that occur due to prolonged consumption of fructose.
Fulltext Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats

Chai HJ, Kiew LV, Chin Y, Norazit A, Mohd Noor S, Lo YL, et al.

Int J Nanomedicine, 2017;12:577-591.
PMID: 28144140 DOI: 10.2147/IJN.S111284

BACKGROUND AND PURPOSE: Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier.
EXPERIMENTAL APPROACH: 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF).
RESULTS: In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state.
CONCLUSION/IMPLICATIONS: The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier.
Fulltext A critical review of pharmacological significance of Hydrogen Sulfide in hypertension

Ahmad A, Sattar MA, Rathore HA, Khan SA, Lazhari MI, Afzal S, et al.

Indian J Pharmacol, 2015 May-Jun;47(3):243-7.
PMID: 26069359 DOI: 10.4103/0253-7613.157106

In the family of gas transmitters, hydrogen sulfide (H2S) is yet not adequately researched. Known for its rotten egg smell and adverse effects on the brain, lungs, and kidneys for more than 300 years, the vasorelaxant effects of H2S on blood vessel was first observed in 1997. Since then, research continued to explore the possible therapeutic effects of H2S in hypertension, inflammation, pancreatitis, different types of shock, diabetes, and heart failure. However, a considerable amount of efforts are yet needed to elucidate the mechanisms involved in the therapeutic effects of H2S, such as nitric oxide-dependent or independent vasodilation in hypertension and regression of left ventricular hypertrophy. More than a decade of good repute among researchers, H2S research has certain results that need to be clarified or reevaluated. H2S produces its response by multiple modes of action, such as opening the ATP-sensitive potassium channel, angiotensin-converting enzyme inhibition, and calcium channel blockade. H2S is endogenously produced from two sulfur-containing amino acids L-cysteine and L-methionine by the two enzymes cystathionine γ lyase and cystathionine β synthase. Recently, the third enzyme, 3-mercaptopyruvate sulfur transferase, along with cysteine aminotransferase, which is similar to aspartate aminotransferase, has been found to produce H2S in the brain. The H2S has interested researchers, and a great deal of information is being generated every year. This review aims to provide an update on the developments in the research of H2S in hypertension amid the ambiguity in defining the exact role of H2S in hypertension because of insufficient number of research results on this area. This critical review on the role of H2S in hypertension will clarify the gray areas and highlight its future prospects.
Fulltext Comparison of high-fat style diet-induced dysregulation of baroreflex control of renal sympathetic nerve activity in intact and ovariectomized female rats: Renal sympathetic nerve activity in high-fat style diet fed intact and ovariectomized female rats

Sucedaram Y, Johns EJ, Husain R, Sattar MA, Abdulla M, Khalilpourfarshbafi M, et al.

Exp Biol Med (Maywood), 2020 05;245(9):761-776.
PMID: 32212858 DOI: 10.1177/1535370220915673

IMPACT STATEMENT: Over activation of renal sensory nerve in obesity blunts the normal regulation of renal sympathetic nerve activity. To date, there is no investigation that has been carried out on baroreflex regulation of renal sympathetic nerve activity in obese ovarian hormones deprived rat model, and the effect of renal denervation on the baroreflex regulation of renal sympathetic nerve activity. Thus, we investigated the role of renal innervation on baroreflex regulation of renal sympathetic nerve activity in obese intact and ovariectomized female rats. Our data demonstrated that in obese states, the impaired baroreflex control is indistinguishable between ovarian hormones deprived and non-deprived states. This study will be of substantial interest to researchers working on the impact of diet-induced hypertension in pre- and postmenopausal women. This study provides insight into health risks amongst obese women regardless of their ovarian hormonal status and may be integrated in preventive health strategies.
Cisplatin-induced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: role of augmented renal alpha-adrenergic responsiveness

Hye Khan MA, Abdul Sattar M, Abdullah NA, Johns EJ

Exp. Toxicol. Pathol., 2007 Nov;59(3-4):253-60.
PMID: 17764917

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.
Chronic treatment with losartan and carvedilol differentially modulates renal vascular responses to sympathomimetics compared to treatment with individual agents in normal Wistar Kyoto and spontaneously hypertensive rats

Abdulla MH, Sattar MA, Abdullah NA, Khan MA, Abdallah HH, Johns EJ

Eur J Pharmacol, 2009 Jun 10;612(1-3):69-74.
PMID: 19356722 DOI: 10.1016/j.ejphar.2009.03.064

This study set out to investigate the impact of chronic cumulative blockade of angiotensin II and adrenoceptors in WKY and SHR and to explore how the renovascular responses to adrenergic and angiotensin II receptor agonists may be interdependent. Rats were treated with either losartan, carvedilol or losartan+carvedilol for 7 days and on day eight, animals were pentobarbitone anaesthetized and prepared for renal haemodynamic study. Dose-response relationships were determined in terms of reduction/elevation in the magnitude of renal blood flow in response to intrarenal arterial injection of dopamine, phenylephrine and isoprenaline. Renal vascular responses were blunted in WKY and SHR treated with either losartan or carvedilol as compared to their untreated counterparts (P<0.05). In the combined treated rats, the vascular responses to isoprenaline and phenylephrine were restored to levels observed in the untreated rats, but the renal vasoconstrictor responses to dopamine decreased (P<0.05) in both WKY and SHR. There was a reduction of (P<0.05) in the magnitude of the isoprenaline induced renal vasodilation in all SHR as compared to WKY groups. The data obtained showed that the renal vascular action of dopamine, phenylephrine and isoprenaline depended on an intact renin-angiotensin system (RAS) in WKY and SHR. Treatment with losartan or carvedilol blunted the renal vasoconstrictor/vasodilator responses to sympathomimetics which was attenuated with the combined treatment. These observations using chronic blockade of adrenergic and angiotensin receptors demonstrated that there was a long standing interdependency between the RAS and sympathetic nervous system (SNS) in determining the responsiveness of the renal vasculature of normal and hypertensive rats.
Influence of cisplatin-induced renal failure on the alpha(1)-adrenoceptor subtype causing vasoconstriction in the kidney of the rat

Khan AH, Sattar MA, Abdullah NA, Johns EJ

Eur J Pharmacol, 2007 Aug 13;569(1-2):110-8.
PMID: 17559832

This study investigated whether the alpha(1)-adrenoceptor subtype(s) mediating the vasoconstrictor actions of the renal sympathetic nerves were altered in rats with cisplatin-induced renal failure. Male Wistar Kyoto rats were used and half received cisplatin (5 mg/kg i.p.) to induce renal failure and were taken for study 7 days later. The renal blood flow reductions caused by electrical renal nerve stimulation and close intra-renal administration of noradrenaline, phenylephrine and methoxamine were determined before and after amlodopine (AMP), 5-methylurapidil (MeU), chloroethylclonidine (CEC) or BMY 7378. Water intake and creatinine clearance were decreased (P<0.05) by 40-50% while fractional excretion of sodium was increased two-fold in the cisplatin treated rats. Mean arterial pressure was higher, 110+/-2 versus 102+/-3 mmHg and renal blood flow was lower, 10.7+/-0.9 versus 18.9+/-0.1 ml/min/kg in the renal failure rats (both P<0.05). AMP, MeU and BMY 7378 decreased (all P<0.05) the adrenergically induced renal vasoconstrictor responses in the renal failure groups by 30 to 50% and in normal rats by 20 to 40%. In the presence of CEC, renal nerve stimulation and noradrenaline and methoxamine induced renal vasoconstrictor responses were enhanced (all P<0.05) in the renal failure but not in the normal rats. These data showed that alpha(1A)- and alpha(1D)-adrenoceptors were the major subtypes in mediating adrenergically induced renal vasoconstriction but there was no substantial shift in subtype in renal failure. The contribution of alpha(1B)-adrenoceptor subtypes either pre- or post-synaptic appeared to be raised in the renal failure rats.

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