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Effect of acacia gum on blood pressure in rats with adenine-induced chronic renal failure.

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Keywords: Gumarabic Adenine Chronic renal failure Rats Blood pressure Lisinopril

ABSTRACT

Chronic renal failure (CRF) occurring naturally in patients or induced by subtotal nephrectomy in rats induces several alterations in the cardiovascular system (CVS). However, the effect of chemically induced CRF in rats on the CVS is less well known. We induced CRF in rats by feeding adenine (0.75%, w/w, four weeks) and investigated the effect of the ensuing CRF on the systolic and diastolic blood pressure (BP) and heart rate (HR). Further, we investigated the effect of giving acacia gum (AG, 10%, w/v) in the drinking water concomitantly with adenine on the above parameters. AG has been previously shown to ameliorate the severity of CRF in humans and rats. We confirmed here that adenine-induced CRF significantly increased the plasma concentrations of urea and creatinine, and reduced creatinine clearance. Additionally, it significantly increased both systolic and diastolic BP, with no significant effect on HR. Both of these actions were significantly mitigated by AG treatment. The antihypertensive angiotenisn-converting enzyme inhibitor lisinopril (10 mg/kg) was given by gavage to rats concomitantly with adenine, significantly reduced the rise in blood pressure induced by adenine. In conclusion, adenine-induced CRF in rats significantly increased BP, and this was significantly mitigated by administration of AG. Possible mechanisms of these changes and the protective effect of AG will be investigated.

[c] 2011 Published by Elsevier GmbH.

Introduction

In humans with chronic kidney disease, and in rats with subtotal nephrectomy-induced chronic renal failure (CRF) several alterations in the cardiovascular system (CVS) are known to occur (He et al., 2009; Ram and Fenves, 2009). In human patients, hypertension is the commonest cardiovascular disease among CRF patients (Redon et al., 2010) and experimental animals (Michea et al., 2008). Other abnormalities include adverse effects on the heart (Kennedy e tal., 2003).

There are two experimental animal models for CRF, viz the surgical model (7/8 remnant kidney model, or RMR) and the chemical model (using adenine in the feed). The effect on the cardiovascular system (CVS) of the latter experimental model, first introduced by Ormond and Miller (1980) (Ormrod and Miller, 1980) and recently used in our laboratory (Ali et al., 2010), has received relatively little attention (Adachi and Nakada, 1999).

We have recently demonstrated that acacia gum (AG) treatment was effective in ameliorating several biochemical and histopathological indices, and motor and behavioral changes in adenine-induced CRF (Ali et at, 2010; Ali et al., 2011). However, the effect of adenine-induced CRF on blood pressure and heart rate in rats, and the possible protective of AG thereon has not been investigated. Consequently, in the present work, we report on the effect of adenine-induced CRFon blood pressure and heart rate, and furthermore, we investigated whether treatment with AG would also mitigate these CVS actions. Moreover, In this study we used the angiotensin-converting enzyme inhibitor (ACEI) Hsinopril as a positive control because ACEIs are known to mitigate both experimental and human renal failure (Benigni etal., 2010). The possible mechanism for the nephroprotective action of AG has been recently reviewed (Ali et al., 2009).

Methods

Animals

Twenty-four male Wistar rats, initially weighing 150-155g, were obtained from our University Animal House and were housed in groups of six under standard temperature (22[+ or -] 2 C), humidity (50-60%), and light conditions (artificial light from 0600 to 1800 h). The rats had seven days to acclimatize to the new surroundings before being treated and tested. They had free access to water and a standard powder diet containing 0.85% phosphorus, 1.12% calcium, 0.35% magnesium, 25.3% crude protein and 2.5 IU/g vitamin D3 (Oman Flour Mills, Muscat, Oman). Body weight was taken at the beginning and the end of the experiment on a top loading balance with a tenth of a gram precision. Procedures involving animals and their care were conducted in conformity with international laws and policies (EEC Council directives 86/609, OJL 358, 1 December, 12, 1987; N1H Guide for the Care and Use of Laboratory Animals, NIH Publications No. 85-23, 1985), and an ethical clearance was obtained from our University Animal Ethics Committee.

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Experimental design

After an acclimatization period of seven days, rats were randomly divided into four equal groups of six rats each. The first group continued to receive the same diet without treatment until the end of the study (control group). The second group was switched to a powder diet containing adenine (0.75% (w/w) in feed) for four weeks. The third group was given normal food and AG in drinking water at a concentration of 10% (w/v) for four weeks. The fourth group was given adenine in the feed together with AG, as above.

A single group was given lisinopril by gavage at a dose of 10 mg/kg concomitantly with adenine.

Just before the treatment and at weekly intervals thereafter, systolic and diastolic blood pressure and heart rates were measured. Twenty-four-h after the end of the treatment period, rats were placed individually in metabolic cages to collect the urine voided in 24 h. Thereafter, the rats were anesthetized with an intraperitoneal injection of ketamine (75 mg/kg) and xylazine (5 mg/kg), and blood (3 ml) collected from the anterior vena cava was placed into heparinized tubes.The blood and urine were centrifuged at 900 gat 4[degrees]C for 15 min. The plasma obtained, together with the urine specimens were stored frozen at -80[degrees]C pending analysis.

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Biochemical measurements

The concentrations of creatinine in plasma and urine, and urea in plasma were measured spectrophotometrically using kits from Human GmbH (Mannheim, Germany).

Blood pressure and heart rate measurements

Two weeks before the experiment, the rats were handled and accustomed to the procedure of blood pressure recording, using non-invasive tail-cuff plethysmography (NIBP Multi Channel Blood Pressure Systems, Woodlands Hills, CA, USA), as used before in our laboratory (Benigni et al., 2010). Briefly, conscious rats were placed in a restrainer on a warming pad and allowed to rest inside the cage for 15min before blood pressure measurements were taken. Rat tails were placed inside a tail cuff, and the cuff was inflated and released three times to allow the animal to be conditioned for the process. Blood pressure was determined at the beginning and at the end of each week for four consecutive weeks.

Drugs and chemicals

Acacia gum (Product code Sigma G9752, 1419328 12209109) and adenine were obtained from Sigma (St. Louis, MO, USA) and aqueous solutions of them were prepared freshly every day. The chemical properties of AG has been fully reviewed before (Ali et al., 2009). Lisinopril was from Astra Zeneca (UK), Creatinine and urea kits were from Human GmbH (Mannheim, Germany). All other chemicals were of analytical reagent grade.

Statistical analysis

Values reported are means [+ or -] SEM (number of observations). Differences between groups were analyzed by a one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison tests (Graphpad Prism version 4.03, San Diego, CA, USA); P < 0.05 was considered statistically significant.

Results

General effects

The body weight changes in the four groups studied. Adenine feeding (0.75% (w/w) for 4 weeks) caused a progressive decrease in body weight amounting to about 47% at the end of the treatment period, when compared with the initial body weight. Concomitant treatment with AG at concentrations of 10% (w/w) in water ameliorated this effect (data not shown). The general appearance of the adenine-treated rats was improved by AG treatment. Kidneys of adenine-treated rats were pale, and a few adenine crystals were seen mainly in the cortexarea. The morphological appearance of the kidneys of rats treated with adenine plus AG at the two doses used was improved compared with that of the kidneys of rats treated with adenine alone. Fig. 1 shows that adenine treatment progressively and significantly increased water intake and urine output. This was reversed by AG treatment.

Biochemical measurements

As shown in Fig. 2, adenine feeding (0.75% (w/w) for 4 weeks) caused significant increases (P < 0.001) in the concentrations of urea and creatinine in plasma, and significant decrease in the creatinine clearance (P < 0.001). Treatment with GA significantly abated the adenine effect.

Effect on blood pressure and heart rate

Adenine feeding (0.75% (w/w) for 4 weeks) significantly increased (P < 0.001) the systolic and diastolic blood pressure (P < 0.001). Treatment with GA significantly abated this effect (Fig. 3). The antihypertensive angiotenisn-converting enzyme inhibitor lisinopril (10mg/kg) was given by gavage to rats concomitantly with adenine significantly (P < 0.001) reduced the rise in blood pressure induced by adenine (Fig. 3).

The results of the effect of adenine-induced CRF on heart rate versus control group were insignificant (Fig. 4).

Discussion

AG is used in some parts of Asia and Africa in the treatment of patients with CRF (Ali et al. 2009) and has been shown experimentally to be beneficial in rats with adenine-induced CRF (Ali et al. 2010), but not in rats with surgically induced CRF (Ali et al. 2004).

CRF is known to cause cardiovascular, behavioral, reproductive and other complications in both patients and the rat model of RMR (Baig et al. 2009; Cho et al. 2009). However, such complications are infrequently documented in rats with adenine-induced CRF. We have recently demonstrated that AG treatment was effective in ameliorating renal dysfunction, and motor and behavioral changes in adenine-induced CRF (Ali et al. 2010,2011). However, the effect of adenine-induced CRF on blood pressure and heart rate in rats, and the possible protective effect of AG thereon has not been reported so far. Thus, in the present work we have recorded, probably for the first time, some signs and symptoms in rats with adenine-induced CRF, and investigated the effect of AG, given at a dose that has been successful in significantly ameliorating the effects of CRF on several indices of renal function.

We have shown that in the CRF model used here, there is evidence of a significant rise in systolic and diastolic blood pressure, with variable and insignificant effects of heart rate. AG was effective in ameliorating these actions. The action of AG might be ascribed to the general improvement that results from treatment with AG, which has been suggested to result in a urea-lowering effect by increasing urea nitrogen (N) excretion in stools, with a concomitant decrease in the total N excreted in urine (Ali et al. 2009). In a recent study, serum butyrate concentrations were increased following treatment with GA in healthy subjects (Matsumoto et al. 2006) and this may have a role in the claimed salutatory effect on creatinine clearance and glomerular filtration rate. The results of clinical trials conducted by the same group seem to suggest that AG has great potential in controlling renal disease by reducing blood pressure. Oxidative stress is established to be a constant feature in CRF, and may be the basis of the ensuing hypertension and other consequences (Vaziri 2004). Some workers have claimed that AG is a strong anti-oxidant agent, and if this can be confirmed, then this action could explain the effectiveness of AG in reducing the rise in BP that have been seen with adenine-induced CRF (Ali et al. 2009). It is also possible (but rather unlikely) that the concomitantly administered AG had somehow impaired the intestinal absorption of the adenine given in the feed, resulting in lower concentration of adenine in blood. This will be tested in future experiments by measuring the plasma concentration of adenine in treated rats. The exact mechanism(s) by which AG reduced BP in adenine-induced CRF is not certain, and is most probably multi-factorial. Further work on these aspects is warranted.

As far as we are aware, no previous reports on the effect of adenine-induced chronic renal failure on blood pressure in rats, or the effect of AG or the ACEI lisinopril have been reported. Lisinopril here was used as a positive control, as drugs affecting the angiotensin system are known to be nephroprotective (Tsunenari et al. 2007; Ziada 2009). The effect of AG in reducing the adenine-induced rise in blood pressure was only slightly less than that of lisinopril, giving support to the reported salutary effect of AG in this type of renal failure.

Acknowledgments

We would like to thank the staff of the Animal House, SQU, for looking after the rats. The work was made possible by funding from the College of Medicine and Health Sciences, SQU, and The Research Council Fund (PC/MED/PHAR/10/01).

0944-7113/$ - see front matter [c]2011 Published by Elsevier GmbH, doi: 10.1016/j.phymed.2011.03.005

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(1) Deceased.

Badreldin H. Ali (a), *. Amal Ziada (b), (1), Isehaq Al Husseni (b), Sumyia Beegam (b), Bader Al-Ruqaishi (a), Abderrahim Nemmar (c)

(a) Department of Pharmacology. Sultan Qaboos University. Al Khod. Oman

(b) Department of Physiology. College of Medicine and Health Sciences, Sultan Qaboos University, Al Khod. Oman

(c) Department of Physiology. Faculty of Medicine, UAEU, United Arab Emirates

* Corresponding author at: Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, 123 Al Khod. Oman.

E-mail address: alibadreldin@hotmail.com (B.H. Ali).

(1) Deceased.
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Author:Ali, Badreldin H.; Ziada, Amal; Husseni, Isehaq Al; Beegam, Sumyia; Al-Ruqaishi, Bader; Nemmar, Abde
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:7UNIT
Date:Oct 15, 2011
Words:2730
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