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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 35  |  Issue : 2  |  Page : 163-172

Potential effects of aliskiren on myocardial infarction on top of hypertension and heart failure in rats


Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt

Date of Submission10-Dec-2016
Date of Acceptance24-Jan-2017
Date of Web Publication17-Aug-2018

Correspondence Address:
Dr. Al-Zahraa Z Elsayed Mohamed
Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Benha, 13511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-208X.239199

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  Abstract 


Background Myocardial infarction (MI) is defined as an irreversible injury or subsequent necrosis of myocardial cells due to interruption of blood supply to a part of the heart. Heart failure (HF) occurs when the heart is unable to pump sufficiently to maintain blood flow to meet the body’s needs. Hypertension is a chronic medical condition in which the blood pressure in the arteries is elevated; it is said to be present when blood pressure values are at or above 140/90 mmHg. Aliskiren is a direct renin inhibitor indicated for the treatment of hypertension.
Aim The present study was designed to evaluate the effects of aliskiren (50 mg/kg, intraperitoneally) on experimentally induced MI in hypertensive rats with HF.
Materials and methods Model of MI: animals were classified into the following groups: normal control group, MI with no medication group (MI was induced by coronary artery ligation), MI l-nitro arginine methyl ester hydrochloride (l-NAME) group (hypertensive infarcted group), and aliskiren-treated MI l-NAME group. Model of HF: animals were classified into the following groups: normal control group, HF group (isoprenaline-induced HF), and aliskiren-treated HF group.
Results Model of MI: aliskiren reduced blood pressure significantly when compared with the MI l-NAME group. It also improved cardiac enzymes (troponin and creatine phosphokinase-MB), ECG changes (heart rate and T-wave voltage), and infarction size when compared with the MI with no medication group and the MI l-NAME group (infarcted groups). Model of HF: it was found that aliskiren significantly reduced blood pressure when compared with the control group. It also significantly reduced heart rate and improved ejection fraction and histopathological changes of the heart compared with the HF group.
Conclusion In this study, aliskiren had antihypertensive effects. It also could have a protective effect against MI and improve HF.

Keywords: heart failure, hypertension and aliskiren, myocardial infarction


How to cite this article:
Elsayed Mohamed AZZ. Potential effects of aliskiren on myocardial infarction on top of hypertension and heart failure in rats. Benha Med J 2018;35:163-72

How to cite this URL:
Elsayed Mohamed AZZ. Potential effects of aliskiren on myocardial infarction on top of hypertension and heart failure in rats. Benha Med J [serial online] 2018 [cited 2018 Oct 18];35:163-72. Available from: http://www.bmfj.eg.net/text.asp?2018/35/2/163/239199




  Introduction Top


Myocardial infarction (MI), commonly known as heart attack, occurs when the blood supply to a part of the heart is interrupted [1]. Cardiovascular diseases including MI cause 12 million deaths throughout the world each year. They cause ∼25–40% of deaths in many Arab countries [2]. MI occurs when an atherosclerotic plaque builds up in the inner lining of a coronary artery and then suddenly ruptures, causing thrombus formation occluding the artery and preventing blood flow [3]. Heart failure (HF), often referred to as congestive heart failure (CHF), occurs when the heart is unable to pump sufficiently to maintain blood flow to meet the body’s needs [4]. HF is caused by any condition that reduces the efficiency of the heart muscle, through damage or overloading. As such, it can be caused by a wide number of conditions including MI, hypertension (HTN), and amyloidosis [5]. HTN is a major cardiovascular risk factor that directly contributes to coronary artery disease (including MI), stroke, CHF, and renal failure [6]. Appropriate control of blood pressure is the cornerstone of both primary and secondary ischemic heart disease prevention. The renin–angiotensin system is a coordinated hormonal cascade in control of cardiovascular, renal, and adrenal functions that govern fluid and electrolyte balance and arterial pressure [7]. Aliskiren is a direct renin inhibitor, decreasing plasma renin activity and inhibiting conversion of angiotensinogen to angiotensin I (Ang I) [8]. Many drugs control blood pressure by interfering with angiotensin or aldosterone [as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers]. However, when these drugs are used chronically, the body increases renin production, which increases blood pressure again [9]. Therefore, pharmacologists have been looking for a drug to inhibit renin directly, and aliskiren is one such drug [10]. The present study was designed to elucidate the beneficial effect of aliskiren on a model of experimentally induced MI in hypertensive rats. This study also aimed to investigate the effect of aliskiren on experimentally induced HF in rats.


  Materials and methods Top


Materials

  1. Animals: 42 adult, male, albino rats weighing 150–250 g (at the beginning of the study) were used. They were acclimatized for one week and were caged in a fully ventilated room (at room temperature). Rats were allowed free access to food (balanced diet) and water in at the Department of Pharmacology, Benha Faculty of Medicine. Rats were randomly subdivided into seven groups (six rats each).
  2. Drugs and chemicals used:
    1. Aliskiren tablets (Novartis, East Hanover, NJ, USA).
    2. l-nitro arginine methyl ester hydrochloride (l-NAME) powder (Sigma chemicals Co., USA).
    3. Isoprenaline HCL (powder) (Sigma Chemicals Co.).
    4. Heparin (ampoule) (Novo Industry, Novo Allé, 2880 Bagsvaerd, Denmark)
    5. Hematoxylin and eosin (E. Merck, Darmastadt, Germany).
    6. Urethane (ethyl carbamate) (white crystals) (Prolabo, Paris, France).
    7. KCl (crystals) (El-Nasr Pharmaceutical Chemical Company, Egypt).


Aliskiren dissolved in distilled water was orally administered to rats [11].

Methods

Part 1: Model of experimentally induced myocardial infarction:

To investigate the effect of aliskiren on MI in hypertensive rats, 24 adult, male, albino rats were used and were divided into the following four groups: group 1 was the normal control group (sham operated and received standard chow diet and tap water with no medication and then surgically dissected without ligation of the coronary artery) [12]; group 2 was the MI with no medication group (after 4 weeks of normal chow diet with no medication, coronary artery ligation was performed) [13]; group 3 was the MI l-NAME group [received l-NAME for 4 weeks (20 mg/kg/day) by gavage [14], and coronary artery ligation was performed at the end of the 4th week]; and group 4 was the aliskiren-treated MI l-NAME group [received l-NAME for 4 weeks (20 mg/kg/day) and aliskiren (150 mg/kg per day, intraperitoneally) [13], and coronary artery ligation was performed at the end of the 4th week].

Method of induction of MI [12]: Rats were anesthetized with urethane at a dose of 1.5–1.75 g/kg body weight. Half of the dose was injected, intraperitoneally to induce rapid onset, and the other half was injected subcutaneously to insure prolonged maintenance of the anesthetic effect. Body temperature was monitored and maintained at 37°C throughout the experimental protocol. After complete anesthesia, rats were placed on their back. The neck was slit open with a ventral midline incision, tracheostomy was performed, and the rats were ventilated with room air from a positive pressure ventilator (Inco, 910, Maker Chamber 5, Mumbai, India) using compressed air at a rate of 70strokes/min and a tidal volume of 10 ml/kg. A left thoracotomy was performed at the fifth intercostal space, and the pericardium was opened to expose the heart. The proximal left anterior descending coronary artery was identified, and then transiently ligated (or tied with a slipknot) 4–5 mm from its origin using a 6–0 prolene suture for a 30-min ischemic period, but without exteriorization of the heart. To allow cardiac reperfusion, microsurgical scissors were used to cut the knot in the ligature (or by releasing the slipknot). After completion of the surgical procedure, the heart was returned to its normal position in the thorax. The rats then underwent 30 min ischemia and 120 min reperfusion, and in sham control rats the procedure was identical, except that the left anterior descending was not transiently ligated.

Measurement of blood pressure [15]: At the start of the above experiment (before induction of MI) and after complete anesthesia, we measured blood pressure as follows: the jugular vein was freed from its surrounding fascia, ligated, and cannulated to a burette filled with saline, which was used for administration of drugs. The carotid artery was freed from its surrounding fascia, and then two loose ligatures were placed, one at either end and around the freed artery. The artery was ligated at the end away from the heart, and the end near the heart was temporarily occluded with a small bulldog clip. Next, halfway across, the artery was cut, and the arterial cannula filled with glucose and heparin solution (20 000 IU/l of 5% glucose solution) was inserted toward the heart. The cannula was connected to the previously calibrated blood pressure transducer, and the pressure was recorded as tracing by oscillography (400 M.D. 4C.; Palmer Bioscience, Washington, District of Columbia, USA). A strain gauge coupler FC137 (Palmar–. Bioscience, 4401 Jackman Road, Toledo, OH, 43612-1529, Northwest, Lucas County) was used.

Electrophysiological parameters: The four-limb electrodes were fixed to the animal’s four limbs, and records were obtained using the standard lead II at a rate of 25 mm/min. ECG tracings were recorded. The use of lead II was more informative (in rats) than other leads. ECG tracings were recorded 2 h after reperfusion [16].

Biochemical parameters: At the end of the experiment, a blood sample of about 4 ml was collected by a heparinized cannula from the right carotid artery [17]. The blood samples were centrifuged at 3000 rpm, and serum was separated. Samples were stored at−20°C in dark containers and subjected to creatine phosphokinase-MB (CPK-MB) and troponin-I measurement.

Histochemical technique: At the end of the experiment, the heart was excised, and the excised beating heart was submerged in cold (∼8°C) 30 mM KCl to achieve diastolic arrest [18]. The right ventricle and both atria were excised to isolate the left ventricle (the septum and the free wall). The left ventricle was then sectioned using a sharp surgical scissor into transverse slices each of about 1.5-mm thickness in a plane parallel to the atrioventricular groove. The slices were then stained with 1.5% triphenyltetrazolium chloride (TTC) in phosphate buffer, pH 7.4, for 10–15 min at 37°C. The TTC stain forms red-colored precipitates in the presence of intact dehydrogenase enzyme systems. Areas of necrosis lack dehydrogenase activity, and therefore do not to stain. The areas with necrosis are clearly discernible, and thus quantifiable. This technique has been used extensively and has been proved to be valid even in the very early phase of MI. The slices were washed with saline, and then clear glass plates were placed over both sides of each slice. Epicardial and endocardial outlines as well as the TTC-stained and nonstained areas were traced on clear plastic sheets. The plastic sheets were then fixed on an ECG paper, and the small squares occupying the stained and nonstained areas were counted in mm2. The sum of stained and nonstained areas gives the surface area of the whole slice. The surface area of the whole left ventricle was calculated by adding the surface areas of all the cardiac sections measured by the ECG paper. The surface area of the infarcted tissue in the whole heart was obtained by adding the surface areas of the infarcted tissue in all cardiac slices, and the infarcted size was calculated as the percentage of the sum of infarcted areas to the sum of the surface areas of all the slices [19].

Model of experimentally induced heart failure [20]

HF was produced in rats by subcutaneous injection of isoprenaline (150 mg/kg) dissolved in saline in the abdominal region. Surviving animals were used for the experiment for 2 weeks after administration of this single overdose.

Eighteen adult, male rats were used and divided into three groups (six rats each). Group 1, the normal control group, was given saline only by subcutaneous injection. Group 2, the HF group, received subcutaneous isoprenaline (150 mg/kg) [20] to induce HF. Group 3, the aliskiren-treated HF group, received subcutaneous isoprenaline (150 mg/kg) to induce HF and aliskiren (50 mg/kg/day, intraperitoneally) [13] for 2 weeks.

Measurement of blood pressure by rat tail method [21]: Rats were conscious during measurement of blood pressure, and were placed in the restrainer for 15–30 min before measurements. The pneumatic cuff was fit over the tail, inflated to occlude the pulse, and allowed to deflate slowly until the pulse pressure was observed on the pulse channel of the laboratory chart. A four-channel recorder was used to obtain a record of both pulse and cuff pressure. The pulse sign should be monitored to see when it becomes detectable and reaches the maximum pulse height; these readings are analogs to systolic blood pressure (SBP) and diastolic blood pressure (DBP).

Echocardiographic measurement: Rats were anaesthetized, and the M-mode and two-dimensional echocardiography images were obtained at high frequency (8–4 MHz). Ejection fraction (EF)=left ventricular end-diastolic volume−(left ventricular end-systolic volume/left ventricular end-diastolic volume)×100 [13].

Histopathological examination: After functional studies were completed, the chest was rapidly opened and the heart was removed as a whole and placed in buffered 4% formalin fixation solution and processed with paraffin wax for histopathological examination. Transverse sections (2-µm thick) of the left ventricular free wall at the papillary muscle level were stained with hematoxylin and eosin, and the stained sections were examined microscopically [17].

Statistical analysis

In the statistical comparison between different groups, the significance of difference was tested using analysis of variance (F value). To compare mean values of more than two groups of quantitative data, a multiple-comparison post-hoc test Least Significant Difference (LSD) was used. A P-value less than 0.05 was considered statistically significant, whereas a value greater than 0.05 was considered statistically insignificant. A P-value less than 0.01 was considered highly significant [22].


  Results Top


The effect of aliskiren on experimentally induced myocardial infarction in hypertensive rats

Measurement of arterial blood pressure (systolic and diastolic)

Administration of l-NAME for 4 weeks resulted in significant increases (P<0.001) in SBP and DBP values in the MI l-NAME group when compared with the control group and the MI with no medication group. Treatment with aliskiren 50 mg/kg, intraperitoneally, for 4 weeks resulted in significant decreases (P<0.001) in SBP and DBP when compared with the MI l-NAME group. There were no significant differences (P>0.05) between the control group, the MI with no medication group, and the aliskiren-treated group ([Table 1]).
Table 1 Effect of treatment with aliskiren 50 mg/kg, intraperitoneally, for 4 weeks on arterial blood pressure, heart rate, and T-wave voltage in a model of experimentally induced myocardial infarction in hypertensive rats (n=6)

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Electrocardiogram changes

Heart rate (HR) at 120 min of reperfusion: Induction of MI by coronary artery ligation followed by 2 h of reperfusion resulted in a significant increase (P<0.001) in HR in the MI with no medication group and the MI l-NAME group when compared with the control group. Treatment with aliskiren resulted in a significant decrease (P<0.001) in HR when compared with the MI with no medication group and the MI l-NAME group, but was significantly high (P<0.001) when compared with the control group ([Table 1]).

T-wave voltage at 120 min of reperfusion: In the MI with no medication group, there was a significant increase (P<0.001) in T-wave voltage after 2 h of reperfusion when compared with the control group, whereas T-wave voltage in the MI l-NAME group was significantly high (P<0.001) when compared with the MI with no medication group and the control group. Treatment with aliskiren resulted in a significant decrease (P<0.001) in T-wave voltage when compared with the MI with no medication group and the MI l-NAME group, but was significantly high (P<0.001) when compared with the control group ([Table 1]).

Measurement of infarction size after 120 min of reperfusion

The infarction size was significantly increased (P<0.001) in the MI with no medication group compared with the control group, whereas the infarction size in the MI l-NAME group was significantly high (P<0.001) when compared with the MI with no medication group and the control group. Treatment with aliskiren resulted in a significant decrease (P<0.001) in infarction size when compared with the MI with no medication group and the MI l-NAME group, but was significantly high (P<0.001) when compared with the control group ([Table 2]).
Table 2 Effect of treatment with aliskiren 50 mg/kg, intraperitoneally, for 4 weeks on infarction size and the serum level of cardiac enzymes (creatine phosphokinase-MB and troponin) in a model of experimentally induced myocardial infarction in hypertensive rats (n=6)

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Measurement of cardiac enzymes after 120 min of reperfusion (serum creatine phosphokinase-MB and troponin levels)

In the MI with no medication group, there was a significant increase (P<0.001) in serum CPK-MB and troponin levels when compared with the control group, whereas in MI l-NAME group serum CPK-MB and troponin levels were significantly high (P<0.001) when compared with the MI with no medication and control groups. Treatment with aliskiren resulted in significant decreases (P<0.001) in serum CPK-MB and troponin levels when compared with the MI with no medication and MI l-NAME groups, but was significantly high when compared with the control group ([Table 2]).

Effect of aliskiren on experimentally induced heart failure

Measurement of arterial blood pressure (systolic and diastolic)

The HF rat model induced by isoprenaline showed a significant (P<0.001) decrease in SBP and DBP in HF untreated rats compared with the control rats. Two weeks of aliskiren administration produced insignificant (P>0.05) changes in SBP and DBP in the aliskiren-treated group compared with the HF untreated rats. SBP and DBP were significantly (P<0.001) reduced in aliskiren-treated rats compared with control rats ([Table 3]).
Table 3 Effect of treatment with aliskiren 50 mg/kg, intraperitoneally, for 2 weeks on arterial blood pressure, heart rate, and ejection fraction in a model of experimentally induced heart failure (n=6)

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Heart rate changes

HR was significantly (P<0.001) increased in HF untreated rats compared with control rats. Two weeks of aliskiren administration decreased HR significantly (P<0.001) compared with HF untreated rats. HR was significantly (P<0.001) increased in aliskiren-treated rats when compared with control rats ([Table 3]).

Ejection fraction

EF was significantly (P<0.001) decreased in HF untreated rats versus control rats. Two weeks of aliskiren administration increased EF significantly (P<0.001) versus the HF untreated rats. EF was significantly (P<0.001) decreased in aliskiren-treated rats compared with control rats ([Table 3] and [Figure 1],[Figure 2],[Figure 3]).
Figure 1 Echocardiographic measurements of the normal control group.

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Figure 2 Echocardiographic measurements of the heart failure group.

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Figure 3 Echocardiographic measurements of the aliskiren-treated heart failure group (50 mg/kg, intraperitoneally, for 2 weeks).

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Histopathological examination

In the HF group, isoprenaline-induced cardiomyocyte degenerative changes in the form of cell swelling and loss of cytoplasmic striations, with interstitial fibrosis, ([Figure 4] and [Figure 5]). Two weeks of aliskiren administration produced a marked decrease in the degenerative changes in the aliskiren-treated HF group ([Figure 6]).
Figure 4 A section of myocardial tissues of the control group. Hematoxylin and eosin, ×40.

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Figure 5 A section of myocardial tissues of the heart failure group showing cardiac myocyte degenerative changes. Hematoxylin and eosin, ×40.

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Figure 6 A section of myocardial tissues of the aliskiren-treated group showing mild hydropic degeneration. Hematoxylin and eosin, ×40.

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  Discussion Top


Myocardial ischemia/reperfusion injury is an important complication of acute coronary arterial occlusion and subsequent recanalization, whether it is spontaneous or therapeutic [23]. CHF is caused by conditions that reduce cardiac output through ischemic damage, increased afterload, or restrictive disease such as MI, HTN, and amyloidosis, respectively [24]. HTN is one of the most important factors associated with the development of several diseases such as HF, renal failure [25], coronary heart disease, atherosclerosis, and MI [26]. Aliskiren blocks the RAAS without inducing a compensatory reaction in Ang I, angiotensin II (Ang II), or plasma renin activity [27]. Thus, treatment with aliskiren may provide protection against MI additional to that achieved by ACE inhibitors or angiotensin receptor blockers [28].

The obtained data in the present study revealed that administration of l-NAME (20 mg/kg/day) for 4 weeks resulted in a significant elevation in blood pressure. These results are in line with El-Nezhawy et al. [29] and Berkban et al. [30], who found that administration of l-NAME resulted in a rapid progressive increase in SBP and DBP that was associated with decreased levels of nitric oxide metabolites in plasma with downregulation of endothelial nitric oxide synthase (eNOS) protein expression compared with control rats.

Data of the present study showed that aliskiren (in a dose of 50 mg/kg) in l-NAME-treated rats caused a significant decrease in blood pressure compared with the l-NAME group. These results are comparable with the study by Rakušan et al. [31], who reported that both aliskiren and losartan fully prevented the development of HTN and cardiac hypertrophy in rats. The antihypertensive effect of aliskiren may be due to increased calcium-dependent eNOS mRNA stability; it also enhances eNOS phosphorylation, decreases NADPH oxidase expression, and restores eNOS uncoupling [32].

In the present study, induction of MI by coronary artery occlusion for 30 min followed by 120 min of reperfusion resulted in significant elevation of HR, T-wave voltage, serum CBK-MB and troponin levels, and infarct size. These results are in agreement with Calvert et al. [33], who reported that myocardial ischemia–reperfusion resulted in significant elevation in serum CPK-MB and troponin levels, and also with the results of Chinda et al. [34], who found significant elevation in HR and infarct size with myocardial ischemia–reperfusion. These data are consistent with Eisenman [35], who observed increased HR and increased CPK-MB levels during MI. In addition, Surawicz [36] reported that the ‘T’ wave was elevated in rats immediately after coronary ischemia and remained elevated for 5 h after ischemia.

The present study showed that MI in l-NAME-induced hypertensive rats produced significant elevation in infarct size, serum CBK-MP and troponin levels, and T-wave voltage compared with MI in normotensive rats. Snoeckx et al. [37] showed enhanced sensitivity to ischemia in hypertrophic hearts. This is may be due to underperfusion of the subendocardial layers of the left ventricle when the coronary circulation is restored after ischemia. Mozaffari and Schaffer [38] found that mechanical function of the reperfused hypertensive heart is severely impaired.

Data obtained from the present study show that treatment with aliskiren 50 mg/kg for 4 weeks produced a significant decrease in serum CPK-MB and troponin levels, infarction size, HR, and T-wave voltage compared with other infarcted nontreated rats. These data are supported by several previous studies such as the study by Bin-Dayel et al. [39], who revealed that treatment with aliskiren significantly increased serum CPK-MB and troponin levels and plasma renin activity in hypertrophied rats with improvement in the histopathological changes of the heart. These results are also in agreement with Yamamoto et al. [40], who found that aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; they also reduced urinary albumin excretion and glomerular inflammation.

Consistent with our results, Koid et al. [41] demonstrated that aliskiren protected the heart from acute cardiac ischemia–reperfusion injury and attenuated cardiac dysfunction with reduction of infarct size independent of change in blood pressure through a bradykinin B2 receptor- and an angiotensin AT2 receptor-mediated mechanism. Aliskiren also increased tissue kallikrein, which in turn increased bradykinin levels in the heart [42], and bradykinin has a well-established cardioprotective activity [43].

The present study showed that treatment with aliskiren significantly reduced HR in the aliskiren-treated group compared with nontreated rats. These data are supported by Yin-yu et al. [44], who found that aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic innervations, and reduced the vulnerability of ventricular arrhythmias after MI. In addition, Ozeki et al. [45] found that aliskiren significantly reduced HR through regulation of the autonomic nervous system in hypertensive patients with ischemic heart disease.

These beneficial actions were explained by the antioxidant properties of aliskiren, the ability to reduce leukocyte accumulation, and an increase in nitric oxide bioavailability by either directly activating NOS through phosphorylation or improving NOS mRNA stability by increasing mRNA half-life and subsequent transcription [46]. Several studies have also shown that aliskiren reduces atherosclerosis in animal models, through improvement in endothelial function [47].

The data in part 2 of the present study revealed that after 2 weeks of high-dose isoprenaline-induced HF, there was a significant increase in HR and reduction of SBP and DBP and EF. Histopathological examination revealed cardiac changes in the form of myocyte necrosis and interstitial fibrosis. These results are in agreement with that obtained by Krenek et al., [48].

In the present study, it was observed that daily administration of aliskiren for 2 weeks produced significant reduction in arterial blood pressure as compared with the control group. On the other hand, this reduction in blood pressure was insignificant as compared with that of the HF group. It also significantly reduced HR and improved EF compared with the HF group. Histopathological examination of the heart sections obviously revealed that aliskiren reduced isoprenaline-induced myocardial damage compared with the HF group.

These results are in line with Yang et al. [49], who reported that aliskiren improved myocardial function in a myocardial ischemia-induced HF model and also improved histopathological changes of the heart. Connelly et al. [50] reported that extracellular matrix deposition and cardiomyocyte hypertrophy as well as EF and left ventricular end-diastolic pressure, key functional indices of HF, were improved by treatment with a combination of ACE and direct renin inhibition.Fischer et al. [51] reported that aliskiren strongly reduced ventricular tachycardia induction, QRS, and QT prolongation and increased T-wave dispersion. Earlier studies have shown that aliskiren reduces plasma renin activity, and thus decreases the level of Ang II [52]. Ang II promotes the release of aldosterone. Both hormones are strong inducers of fibrosis and inflammation that contribute to the pathogenesis of HF and electrical remodeling, sudden cardiac death, and arrhythmias [53].

Consistent with our results, Parodi-Rullan et al. [13] also reported that treatment with aliskiren after HF in rats improved cardiac function (EF) and diminished cardiac hypertrophy. This antiremodeling effect of aliskiren was explained by its ability to improve respiratory function of mitochondria through Ang II-dependent and Ang II-independent mechanisms. Inhibition of renin activity by aliskiren diminishes Ang I production, which is the first and rate-limiting process of the renin–angiotensin system. As a result, reduced levels of Ang II could attenuate the remodeling and hypertrophic response of the heart [54]. The Ang II-independent effect of aliskiren could be mediated through inhibition of binding of renin to the prorenin/renin receptor to prevent upregulation of profibrotic genes independent of Ang II generation [55]. Aliskiren exerted potent antifibrotic effects in the myocardium through both systemic effects on RAAS and direct effects on cardiac fibroblast biology [56].

In conclusion, it was found that treatment with aliskiren was effective in controlling systemic blood pressure which was proved by reduced blood pressure in rats treated with aliskiren when compared with those receiving l-NAME. In addition, aliskiren had protective effects against MI, which was proved by lowered leakage of cardiac biomarkers (CPK-MB and troponin level) and reduction in ECG changes of the heart as well as T-wave voltage with reduction in infarction size in the aliskiren-treated group in comparison with other infarcted nontreated groups. Aliskiren also improved HF, which was proved by reduction in HR and EF with improvement in the histopathological picture of the heart in the aliskiren-treated group when compared with the HF group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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