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Antidiuretic and antinatriuretic response to high salt load in normotensive Wistar-Kyoto rats: Role of alpha-1A-adrenoreceptors

Kazi RN, Sattar MA, Johns EJ

Auton Autacoid Pharmacol, 2017 Jan;37(1):13-18.
PMID: 28332265 DOI: 10.1111/aap.12053

Altered renal adrenergic responses have been recognized as pathophysiological responses to high salt intake. This study aims to investigate the influence of 6 weeks of high salt diet on α1A -adrenoceptor regulation of renal tubular antinatriuretic and antidiuretic response in normal Wistar Kyoto rats. To achieve the above objective, antinatriuretic and antidiuretic response to phenylephrine was measured in the absence and presence of 5-methylurapidil (5-MeU) using the inulin clearance method. Systemic mean arterial blood pressure and renal haemodynamics were also measured simultaneously. Six weeks of high salt intake in Wistar-Kyoto (WKY) rats did not bring any significant increase in mean arterial blood pressure. WKY rat on high salt diet (WKYHNa) showed an exaggerated increase in absolute and fractional sodium excretion. There was a significant involvement of α1A -adrenoceptor in carrying out renal tubular antinatriuretic and antidiuretic response in Wistar Kyoto rats on normal sodium diet (WKYNNa). However, α1A -adrenoceptor played a minimal role in handling the tubular reabsorptive response in WKY rats on high salt diet.
Alpha1A- and alpha1D-adrenoceptors are the major functional subtypes of renal alpha1-adrenoceptors in streptozotocin-induced diabetic and normal Sprague-Dawley rats

Armenia, Sattar MA, Abdullah NA, Khan MA, Johns EJ

Auton Autacoid Pharmacol, 2008 Jan;28(1):1-10.
PMID: 18257746 DOI: 10.1111/j.1474-8673.2007.00412.x

1 The present study investigated the effect of streptozotocin-induced diabetes on alpha(1)-adrenoceptor subtypes in rat renal resistance vessels. 2 Studies on renal haemodynamics were carried out 7 days after the last streptozotocin. Changes in renal blood flow were recorded in response to electrical stimulation of the renal nerve (RNS) and a range of adrenergic agonists; noradrenaline (NA), phenylephrine (PE) and methoxamine (MTX), either in the absence or the presence of nitrendipine (Nit), 5-methylurapidil (MEU), chlorethylclonidine (CEC) or BMY 7378. 3 In non-diabetic animals, Nit, MEU and BMY 7378 significantly attenuated renal vasoconstriction induced by adrenergic agonists, while CEC showed a significant accentuation in RNS-induced responses without having a significant effect on responses to adrenergic agonists. In diabetic rats, renal vasoconstriction was also significantly reduced in Nit-, MEU- and BMY 7378-treated groups and CEC potentiated RNS-induced contractions caused a change similar to that observed in non-diabetic rats. BMY 7378 significantly (P < 0.05) attenuated the PE- and MTX-induced vasoconstrictions but did not cause any significant (P > 0.05) alteration in the RNS- and NA-induced responses. 4 The results showed functional co-existence of alpha(1A)- and alpha(1D)-adrenoceptors in the renal vasculature of SD rats irrespective of the presence of diabetes. A possible minor contribution of prejunctional alpha-adrenoceptor subtype has also been suggested in either experimental group, particularly possible functional involvement of alpha(1B)-adrenoceptor subtypes in non-diabetic SD rats.
Fulltext Influence of combined hypertension and renal failure on functional alpha(1)-adrenoceptor subtypes in the rat kidney

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

Br J Pharmacol, 2008 Mar;153(6):1232-41.
PMID: 18246093 DOI: 10.1038/bjp.2008.13

This study investigated whether the alpha(1)-adrenoceptor responsiveness of the renal vasculature was altered in the state of hypertension combined with renal failure.
The contribution of adrenoceptor subtype(s) in the renal vasculature of diabetic spontaneously hypertensive rats

Armenia A, Munavvar AS, Abdullah NA, Helmi A, Johns EJ

Br J Pharmacol, 2004 Jun;142(4):719-26.
PMID: 15172958

1. Diabetes and hypertension are both associated with an increased risk of renal disease and are associated with neuropathies, which can cause defective autonomic control of major organs including the kidney. This study aimed to examine the alpha(1)-adrenoceptor subtype(s) involved in mediating adrenergically induced renal vasoconstriction in a rat model of diabetes and hypertension. 2. Male spontaneously hypertensive rats (SHR), 220-280 g, were anaesthetized with sodium pentobarbitone 7-day poststreptozotocin (55 mg x kg(-1) i.p.) treatment. The reductions in renal blood flow (RBF) induced by increasing frequencies of electrical renal nerve stimulation (RNS), close intrarenal bolus doses of noradrenaline (NA), phenylephrine (PE) or methoxamine were determined before and after administration of nitrendipine (Nit), 5-methylurapidil (5-MeU), chloroethylclonidine (CEC) and BMY 7378. 3. In the nondiabetic SHR group, mean arterial pressure (MAP) was 146+/-6 mmHg, RBF was 28.0+/-1.4 ml x min(-1) x kg(-1) and blood glucose was 112.3+/-4.7 mg x dl(-1), and in the diabetic SHR Group, MAP was 144+/-3 mmHg, RBF 26.9+/-1.3 ml(-1) min x kg(-1) and blood glucose 316.2+/-10.5 mg x dl(-1). Nit, 5-MeU and BMY 7378 blunted all the adrenergically induced renal vasoconstrictor responses in SHR and diabetic SHR by 25-35% (all P<0.05), but in diabetic rats the responses induced by RNS and NA treated with 5-MeU were not changed. By contrast, during the administration of CEC, vasoconstrictor responses to all agonists were enhanced by 20-25% (all P<0.05) in both the SHR and diabetic SHR. 4. These findings suggest that alpha(1A) and alpha(1D)-adrenoceptor subtypes contribute in mediating the adrenergically induced constriction of the renal vasculature in both the SHR and diabetic SHR. There was also an indication of a greater contribution of presynaptic adrenoceptors, that is, alpha(1B)-, and/or alpha(2)-subtypes.
The effect of losartan and carvedilol on vasopressor responses to adrenergic agonists and angiotensin II in the systemic circulation of Sprague Dawley rats

Abdulla MH, Sattar MA, Abdullah NA, Khan MA, Anand Swarup KR, Johns EJ

Auton Autacoid Pharmacol, 2011 Jan-Apr;31(1-2):13-20.
PMID: 21166975 DOI: 10.1111/j.1474-8673.2010.00461.x

1 Interaction between renin-angiotensin (RAS) and sympathetic nervous systems (SNS) was investigated by examining the effect of cumulative blockade of angiotensin II (Ang II) and adrenergic receptors in normal Sprague Dawley rats. 2 Rats were treated with losartan (10 mg/kg), carvedilol (5 mg/kg), or losartan plus carvedilol (10+5 mg/kg) orally for 7 days. On day 8, the animals were anaesthetized with pentobarbitone and prepared for systemic haemodynamic study. Dose-response relationships for the elevation of mean arterial pressure or change in heart rate (HR) in response to intravenous injections of noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined. 3 Losartan or the combination of losartan with carvedilol blunted vasopressor responses to ME and Ang II. Dose-response relationships for agonist action on HR were significantly inhibited by all treatments except for the combination of losartan and carvedilol on the decrease in HR induced by PE. Carvedilol decreased vasopressor responses to NA, PE and Ang II, and HR responses to NA, ME and Ang II. Combination treatment produced similar effects to losartan on the vasopressor and HR responses but had a greater effect on vasopressor responses to ME and Ang II, and on HR responses to NA and Ang II than carvedilol alone. 4 It is concluded that peripheral vasoconstriction induced by Ang II is partly mediated by adrenergic action and that the vasopressor responses to adrenergic agonists depend on an intact RAS. These observations suggest an interactive relationship between RAS and SNS in determining systemic haemodynamic responses in 'normal' rats.
Influence of high dietary sodium intake on the functional subtypes of alpha-adrenoceptors in the renal cortical vasculature of Wistar-Kyoto rats

Kazi RN, Munavvar AS, Abdullah NA, Khan AH, Johns EJ

Auton Autacoid Pharmacol, 2009 Jan;29(1-2):25-31.
PMID: 19302553 DOI: 10.1111/j.1474-8673.2009.00428.x

1 Increased renal vascular resistance is one renal functional abnormality that contributes to hypertension, and alpha(1)-adrenoceptors play a pivotal role in modulating this renal vascular resistance. This study investigates the functional contribution of alpha(1)-adrenoceptor subtypes in the renal cortical vasculature of Wistar-Kyoto rats on a normal sodium diet (WKYNNa) compared with those given saline to drink for 6 weeks (WKYHNa). 2 The renal cortical vascular responses to the adrenergic agonists noradrenaline (NA), methoxamine (ME) and phenylephrine (PE) were measured in WKYHNa and WKYNNa rats either in the absence (the control phase) or presence of chloroethylclonidine (CEC), an alpha(1B)-adrenoceptor antagonist, 5-methylurapidil (5-MeU), an alpha(1A) antagonist, or BMY7378, an alpha(1D) antagonist. 3 Results showed a greater renal cortical vascular sensitivity to NA, PE and ME in the WKYHNa compared with WKYNNa rats (P < 0.05). Moreover, 5-MeU and BMY7378 attenuated adrenergically induced renal cortical vasoconstriction in WKYHNa and WKYNNa rats; this response was largely blunted in CEC-treated WKYHNa rats (all P < 0.05) but not in CEC-treated WKYNNa rats. 4 The data suggest that irrespective of dietary sodium content, in Wistar-Kyoto rats alpha(1A)- and alpha(1D)-subtypes are the major alpha(1)-adrenoceptors in renal cortical vasculature; however, there appears to be a functional involvement of alpha(1B)-adrenoceptors in the WKYHNa rats.
Influence of sympathetic and AT-receptor blockade on angiotensin II and adrenergic agonist-induced renal vasoconstrictions in spontaneously hypertensive rats

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

Acta Physiol (Oxf), 2009 Mar;195(3):397-404.
PMID: 19183357 DOI: 10.1111/j.1748-1716.2008.01895.x

This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR).
Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats

Abdulla MH, Sattar MA, Salman IM, Abdullah NA, Ameer OZ, Khan MA, et al.

Auton Autacoid Pharmacol, 2008 Apr-Jul;28(2-3):87-94.
PMID: 18598290 DOI: 10.1111/j.1474-8673.2008.00421.x

1 This study was undertaken to characterize the renal responses to acute unilateral renal denervation in anaesthetized spontaneously hypertensive rats (SHR) by examining the effect of acute unilateral renal denervation on the renal hemodynamic responses to a set of vasoactive agents and renal nerve stimulation. 2 Twenty-four male SHR rats underwent acute unilateral renal denervation and the denervation was confirmed by significant drop (P < 0.05) in renal vasoconstrictor response to renal nerve stimulation along with marked diuresis and natriuresis following denervation. After 7 days treatment with losartan, the overnight fasted rats were anaesthetized (sodium pentobarbitone, 60 mg kg(-1) i.p.) and renal vasoconstrictor experiments were performed. The changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine, methoxamine and angiotensin II. 3 The data showed that there was significantly (all P < 0.05) increased renal vascular responsiveness to the vasoactive agents in denervated rats compared to those with intact renal nerves. In losartan-treated denervated SHR rats, there were significant (all P < 0.05) reductions in the renal vasoconstrictor responses to neural stimuli and vasoactive agents as compared with that of untreated denervated SHR rats. 4 The data obtained in denervated rats suggested an enhanced sensitivity of the alpha(1)-adrenoceptors to adrenergic agonists and possible increase of AT(1) receptors functionality in the renal vasculature of these rats. These data also suggested a possible interaction between sympathetic nervous system and renin-angiotensin system in terms of a crosstalk relationship between renal AT(1) and alpha(1)-adrenoceptor subtypes.
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.
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.
Obesity depresses baroreflex control of renal sympathetic nerve activity and heart rate in Sprague Dawley rats: role of the renal innervation

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

Acta Physiol (Oxf), 2015 Jul;214(3):390-401.
PMID: 25846561 DOI: 10.1111/apha.12499

AIM:
This study investigated the role of the renal innervation in arterial and cardiopulmonary baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) in rats fed a high-fat diet to induce obesity.

METHODS:
Rats received either a normal (12% kcal) or high (45% kcal) fat diet for 60 days. On day 61, rats were anesthetized and prepared for recording left RSNA. In one group, the renal nerves remained intact, while in the other, both kidneys were denervated. Baroreflex gain curves for RSNA and HR were generated by increasing and decreasing blood pressure. Low-pressure baroreceptors were challenged by infusing a saline load.

RESULTS:
Mean blood pressure was 135 mmHg in the fat-fed and 105 mmHg (P < 0.05) in normal rats. Weight gain, adiposity index and creatinine clearance were 37, 82 and 55% higher (P < 0.05-0.001), but urine flow rate and fractional sodium excretions were 53 and 65% (both P < 0.001) lower, respectively, in the fat-fed compared to normal rats. In fat-fed rats with innervated kidneys, RSNA and HR arterial baroreflex sensitivities were reduced by 73 and 72% (both P < 0.05) but were normal in renally denervated rats. Volume expansion decreased RSNA by 66% (P < 0.001) in normal rats, but not in the intact fat-fed rats and by 51% (P < 0.01) in renally denervated fat-fed rats.

CONCLUSION:
Feeding a high-fat diet caused hypertension associated with dysregulation of the arterial and cardiopulmonary baroreflexes which was dependent on an intact renal innervation. This suggests that in obese states neural signals arising from the kidney contribute to a deranged autonomic control.

KEYWORDS:
baroreflex gain curves; cardiopulmonary reflex; high-fat diet
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.
Improvement in baroreflex control of renal sympathetic nerve activity in obese Sprague Dawley rats following immunosuppression

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

Acta Physiol (Oxf), 2017 Dec;221(4):250-265.
PMID: 28456134 DOI: 10.1111/apha.12891

AIM: This investigation explored the hypothesis that in obesity an inflammatory response in the kidney contributed to a renal nerve-dependent blunting of the baroreflex regulation of renal sympathetic nerve activity.
METHODS: Rats received a normal (12% kcal) or high-fat (45% kcal) diet for 8 weeks plus daily injections of vehicle (0.9% NaCl i.p) or tacrolimus (0.25 mg kg-1 day-1 i.p) from weeks 3-8. Following anaesthesia, left renal sympathetic nerve activity was recorded, baroreflex gain curves were generated, by infusing phenylephrine and sodium nitroprusside, and cardiopulmonary baroreceptors challenged by infusing a saline load.
RESULTS: The high-fat diet elevated weight gain and adiposity index by 89 and 129% (both, P < 0.001). Mean blood pressure (132 ± 4 vs 103 ± 5 mmHg), fractional noradrenaline excretion and creatinine clearance (5.64 ± 0.55 vs 3.32 ± 0.35 mL min-1 kg-1 ) were 28, 77 and 69% higher (all P < 0.05), but urine flow and fractional sodium excretions were 42 and 72% (both P < 0.001) lower compared to normal rats. Plasma and renal TNF-α and IL-6 concentrations were fourfold to fivefold (P < 0.001) and 22 and 20% higher (both, P < 0.05), in obese rats but normalized following tacrolimus. In obese rats, baroreflex sensitivity was reduced by 80% (P < 0.05) but restored by renal denervation or tacrolimus. Volume expansion reduced renal sympathetic nerve activity by 54% (P < 0.001) in normal and obese rats subjected to renal denervation and tacrolimus, but not in obese rats with an intact renal innervation.
CONCLUSION: Obesity induced a renal inflammation and pointed to this being both the origin of autonomic dysregulation and a potential focus for targeted therapy.
Renal denervation restores the baroreflex control of renal sympathetic nerve activity and heart rate in Wistar-Kyoto rats with cisplatin-induced renal failure

Khan SA, Sattar MA, Rathore HA, Abdulla MH, Ud Din Ahmad F, Ahmad A, et al.

Acta Physiol (Oxf), 2014 Mar;210(3):690-700.
PMID: 24438102 DOI: 10.1111/apha.12237

There is evidence that in chronic renal failure, the sympathetic nervous system is activated. This study investigated the role of the renal innervation in suppressing high- and low-pressure baroreflex control of renal sympathetic nerve activity and heart rate in cisplatin-induced renal failure.
Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats

Abdulla MH, Sattar MA, Abdullah NA, Hazim AI, Anand Swarup KR, Rathore HA, et al.

Auton Autacoid Pharmacol, 2008 Oct;28(4):95-101.
PMID: 18778332 DOI: 10.1111/j.1474-8673.2008.00422.x

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.
Inhibition of L-NAME-induced hypertension by combined treatment with apocynin and catalase: the role of Nox 4 expression

Chia TY, Murugaiyah V, Khan NA, Sattar MA, Abdulla MH, Johns EJ, et al.

Physiol Res, 2021 03 17;70(1):13-26.
PMID: 33728924

Reactive oxygen species (ROS) such as superoxide (O2-) generated by NAD(P)H oxidases have emerged as important molecules in blood pressure regulation. This study investigated the effect of apocynin and catalase on blood pressure and renal haemodynamic and excretory function in an L-NAME induced hypertension model. Forty Male Wistar-Kyoto (WKY) rats (n=8 per group) were treated with either: vehicle (WKY-C); L-NAME (WKY-L, 15 mg/kg/day in drinking fluid); WKY-L given apocynin to block NAD(P)H oxidase (WKY-LApo, 73 mg/kg/day in drinking water.); WKY-L given catalase to enhance ROS scavenging (WKY-LCat, 10000 U/kg/day i.p.); and WKY-L receiving apocynin plus catalase (WKY-LApoCat) daily for 14 days. L-NAME elevated systolic blood pressure (SBP), 116+/-1 to 181±4 mmHg, reduced creatinine clearance, 1.69+/-0.26 to 0.97+/-0.05 ml/min/kg and fractional sodium excretion, 0.84+/-0.09 to 0.55+/-0.09 % at day 14. Concomitantly, plasma malondialdehyde (MDA) increased six fold, while plasma total superoxide dismutase (T-SOD), plasma nitric oxide (NO) and plasma total antioxidant capacity (T-AOC) were decreased by 60-70 % and Nox 4 mRNA expression was increased 2-fold. Treatment with apocynin and catalase attenuated the increase in SBP and improved renal function, enhanced antioxidative stress capacity and reduced the magnitude of Nox4 mRNAs expression in the L-NAME treated rats. This study demonstrated that apocynin and catalase offset the development of L-NAME induced hypertension, renal dysfunction and reduced oxidative stress status, possibly contributed by a reduction in Nox4 expression during NOS inhibition. These findings would suggest that antioxidant compounds such as apocynin and catalase have potential in treating cardiovascular diseases.
The restorative effect of apocynin and catalase in l-arginine induced hypotension on normotensive subjects - the role of oxidative stress

Chia TY, Murugaiyah V, Sattar MA, Khan NAK, Ahmad A, Abdulla MH, et al.

Physiol Res, 2020 12 22;69(6):1051-1066.
PMID: 33210935

L-arginine is a substrate for nitric oxide synthase (NOS) responsible for the production of NO. This investigation studied the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on L-arginine induced oxidative stress and hypotension. Forty Wistar-Kyoto rats were treated for 14 days with vehicle, L-arginine (12.5mg/ml p.o.), L-arginine+apocynin (2.5mmol/L p.o.), L-arginine+catalase (10000U/kg/day i.p.) and L-arginine plus apocynin+catalase respectively. Weekly renal functional and hemodynamic parameters were measured and kidneys harvested at the end of the study for histopathological and renal NADPH oxidase 4 (Nox4) assessments. L-arginine administration in normotensive rats decreased systolic blood pressure (120±2 vs 91±2mmHg) and heart rate (298±21 vs 254±15b/min), enhanced urinary output (21.5±4.2 vs 32±1.9ml/24h , increased creatinine clearance (1.72±0.56 vs 2.62±0.40ml/min/kg), and fractional sodium excretion (0.88±0.16 vs 1.18±0.16 %), caused proteinuria (28.10±1.93 vs 35.26±1.69mg/kg/day) and a significant decrease in renal cortical blood perfusion (292±3 vs 258±5bpu) and pulse wave velocity (3.72±0.20 vs 2.84±0.13m/s) (all P<0.05). L-arginine increased plasma malondialdehyde (by ~206 % P<0.05) and NO (by~51 %, P<0.05) but decreased superoxide dismutase (by~31 %, P<0.05) and total antioxidant capacity (by~35 %, P<0.05) compared to control. Renal Nox4 mRNA activity was approximately 2.1 fold higher (P<0.05) in the L-arginine treated rats but was normalized by apocynin and apocynin plus catalase treatment. Administration of apocynin and catalase, but not catalase alone to rats fed L-arginine, restored the deranged renal function and structure, prevented hypotension and enhanced the antioxidant capacity and suppressed Nox4 expression. These findings suggest that apocynin and catalase might be used prophylactically in states of oxidative stress.
Role of norepinephrine & angiotensin II in the neural control of renal sodium & water handling in spontaneously hypertensive rats

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

Indian J Med Res, 2010 Jun;131:786-92.
PMID: 20571167

A wealth of information concerning the essential role of renal sympathetic nerve activity (RSNA) in the regulation of renal function and mean arterial blood pressure homeostasis has been established. However, many important parameters with which RSNA interacts are yet to be explicitly characterized. Therefore, the present study aimed to investigate the impact of acute renal denervation (ARD) on sodium and water excretory responses to intravenous (iv) infusions of either norepinephrine (NE) or angiotensin II (Ang II) in anaesthetized spontaneously hypertensive rats (SHR).
Interaction between renin-angiotensin and sympathetic nervous systems in a rat model of pressure overload cardiac hypertrophy

Rathore HA, Munavvar AS, Abdullah NA, Khan AH, Fathihah B, NurJannah MH, et al.

Auton Autacoid Pharmacol, 2009 Oct;29(4):171-80.
PMID: 19740088 DOI: 10.1111/j.1474-8665.2009.00445.x

1 A raised cardiac workload activates neurohormones which will increase muscle mass and shift contractility to the right along the Frank-Starling curve. 2 This study examined the interaction between the SNS and RAS in contributing to vascular responsiveness following the development of cardiac hypertrophy due to aortic banding. 3 Sprague Dawley rats (180-200 g) were assigned to one of six groups; Normal, Sham-operated, Aortic Banded (AB), Aortic Banded treated with losartan (ABLOS), Aortic Banded treated with 6-hydroxydopamine (ABSYMP) and Aortic banded treated with both losartan and 6-hydroxydopamine (ABSYMPLOS). A constricting band was placed around the supra renal aorta on day zero with drug treatment from day 37 to day 44. Vasopressor responses to noradrenaline, phenylephrine, methoxamine and angiotensin II were measured on day 45. 4 The magnitudes of the MAP responses to all vasoactive agents, expressed as percentage changes, were similar in Normal and Sham groups, but reduced in the AB group. ABLOS group showed attenuated response to ANGII whereas all responses were enhanced in the ABSYM group. 5 A positive interaction between the two systems was observed with alpha(1A)-adrenoceptors identified as a major component of SNS and AT(1) receptors of RAS to induce vasopressor effects.
Fulltext Alterations of haemodynamic parameters in spontaneously hypertensive rats by Aristolochia ringens Vahl. (Aristolochiaceae)

Aigbe FR, Munavvar ASZ, Rathore H, Eseyin O, Pei YP, Akhtar S, et al.

J Tradit Complement Med, 2018 Jan;8(1):72-80.
PMID: 29321992 DOI: 10.1016/j.jtcme.2017.02.006

Aristolochia ringens Vahl. (Aristolochiaceae (AR); mǎ dōu líng) is used traditionally in Nigeria for the management of various disorders including oedema. Preliminary investigation revealed its modulatory effect on the cardiovascular system. This study was aimed at investigating the effect of the aqueous root extract of A. ringens (AR) on haemodynamic parameters of spontaneously hypertensive rats (SHRs). The effect of oral subacute (21 days) and intravenous acute exposure of SHRs to the extract were assessed using tail cuff and carotid artery canulation methods respectively. In the latter, the effect of chloroform, butanol and aqueous fractions of AR were also evaluated. The extract significantly reduced systolic and diastolic blood pressures in SHRs, with peak reductions of 20.3% and 26.7% respectively at 50 mg/kg by the 21st day of oral subacute exposure. Upon intravenous exposure, AR (50 mg/kg) reduced systolic and diastolic blood pressure by as much as 53.4 ± 2.2 and 49.2 ± 2.8 mmHg respectively. A dose-dependent reduction in heart rate, significant at 25 and 50 mg/kg was also observed. Hexamethonium (20 mg/kg) and atropine (1 mg/kg) inhibited the extract's reduction of systolic blood pressure, diastolic blood pressure and heart rate significantly. The extract's butanol fraction produced the greatest systolic and diastolic blood pressures reduction of 67.0 ± 3.8 and 68.4 mmHg respectively at 25 mg/kg and heart rate reduction of 40 ± 7 beats per minute at 50 mg/kg. HPLC analysis revealed the presence of 4-hydroxybenzoic acid and quercetin in AR. The extract's alterations of haemodynamic parameters in this study show that it has hypotensive effect on spontaneously hypertensive rats.

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