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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 35  |  Issue : 3  |  Page : 317-325

Effect of ambroxol on experimentally induced acute oxidative stress in the heart, kidney, and intestine in rats


1 Professor of Pharmacology, Benha University, Egypt
2 Asistant Professor of Pharmacology, Benha University, Egypt
3 Lecturer of Pharmacology, Benha University, Egypt
4 MSc in Pharmacology, Benha University, Egypt

Date of Submission12-Aug-2017
Date of Acceptance02-Oct-2017
Date of Web Publication07-Jan-2019

Correspondence Address:
Dr. Manar A Metwally
Menoufia, Quesna, 13511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bmfj.bmfj_163_17

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  Abstract 


Background Intestinal ischemia–reperfusion (IR) is a frequently occurring phenomenon during abdominal and thoracic vascular surgery, small bowel transplantation, hemorrhagic shock, and surgery using cardiopulmonary bypass, carrying high morbidity and mortality. Ambroxol hydrochloride is an active N-desmethyl metabolite of bromhexine hydrochloride. Ambroxol is indicated as ‘secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport’.
Aim The present study was designed to evaluate the effect of ambroxol on experimentally induced acute organ oxidative stress in the form of remote organ injury including kidney and heart after intestinal IR.
Materials and methods Thirty animals were classified into five groups. First group: normal control group, second group: nontreated intestinal IR group (intestinal IR was induced by mesenteric artery ligation), third group: ambroxol pretreated intestinal IR group (35 mg/kg), fourth group: ambroxol pretreated intestinal IR group (70 mg/kg), fifth group: ambroxol pretreated intestinal IR group (140 mg/kg).
Results Ambroxol significantly reduced the malondialdehyde level in the heart and the kidney when compared with intestinal IR with no medication group. It also improved cardiac troponin and, kidney functions (urea and creatinine) and histopathological affection when compared with intestinal IR with no medication group. Conclusively, in this study ambroxol could have a protective effect against intestinal IR through its antioxidative and anti-inflammatory effect.

Keywords: ambroxol, intestinal ischemia–reperfusion, malondialdehyde and cardiac troponin 1, oxidative stress


How to cite this article:
Elfouli MM, Said ME, Emam HT, Abu-raia NH, Metwally MA. Effect of ambroxol on experimentally induced acute oxidative stress in the heart, kidney, and intestine in rats. Benha Med J 2018;35:317-25

How to cite this URL:
Elfouli MM, Said ME, Emam HT, Abu-raia NH, Metwally MA. Effect of ambroxol on experimentally induced acute oxidative stress in the heart, kidney, and intestine in rats. Benha Med J [serial online] 2018 [cited 2019 Dec 15];35:317-25. Available from: http://www.bmfj.eg.net/text.asp?2018/35/3/317/249418




  Introduction Top


Intestinal ischemia is a life-threatening condition associated with a broad range of clinical conditions including atherosclerosis, thrombosis, hypotension, necrotizing enterocolitis, bowel transplantation, trauma, and chronic inflammation [1]. The majority of ischemic episodes seen in clinics in the western world are due to thromboembolic or artherothrombotic vaso-occlusive disease. The major risk factors for such events are advancing age, male sex, and hereditary factors. However, other important risk factors can be modified or controlled, including tobacco smoking, hyperlipidemia, hypertension, physical inactivity, obesity, metabolic syndrome, and diabetes mellitus. Ethanol intake at high levels (3–4 or more drinks), either in acute or chronic (daily) settings, also increases the risk for myocardial infarction and ischemic stroke [2].

The ischemia and reperfusion (IR) syndrome performs a fundamental role in the pathophysiology of several clinical–surgical conditions and may be caused by intestinal intussusception, acute mesenteric arterial occlusion, transplants of the small intestine, and hemodynamic shock [3]. Ambroxol has important pharmacological properties as surfactant stimulatory, anti-inflammatory, antioxidant, and local anesthetic effects in addition to the mucokinetic and mucociliary effects. Recognition of the surfactant stimulatory and anti-inflammatory properties of the drug has led to the importance of the drug in the management of obstructive airway disorders [4]. The present study was designed to evaluate the effect of ambroxol on experimentally induced acute organ oxidative stress in remote organs such as kidney and heart after intestinal IR in adult rats.


  Materials and methods Top


Materials

  1. Animals: 30 adult male albino rats weighing between 150 and 250 g (at the beginning of the study) were used. They have been acclimatized for 1 week and were caged in fully ventilated rooms (at room temperature). Rats were allowed free access to food (balanced diet) and water in the Pharmacology Department, Benha Faculty of Medicine. Rats were randomly subdivided into five groups (six rats each).
  2. Drugs and chemicals:
    1. Ambroxol (powder): October Pharma, Giza, Egypt.
    2. Hematoxylin and eosin: (E. Merck, Darmstadt, Indiana, USA).
    3. Urethane (ethyl carbamat): (white crystals) (Prolabo, Paris, France). White crystals 0.6 g/100 ml of 25% freshly prepared solution.
    4. Urea kits: Diamond Diagnostic, Egypt.
    5. Creatinine kits: Diamond Diagnostic.
    6. Phenobarbital sodium.


Ambroxol was dissolved in distilled water and was given to rats by intravenous injection in intestinal IR model. The procedures were reviewed and approved by the research ethical committee of animal care and use of Benha faculty of medicine, Benha university.

Methods

To investigate the effect of ambroxol on intestinal IR, 30 adult male albino rats are used and divided into five groups. Group 1: control normal group (sham operated). Adult rats were anesthetized with intraperitoneal pentobarbital sodium (50 mg/kg), and a cannula was inserted into the tail vein. A midline laparotomy was performed [5].

Group 2: nontreated intestinal IR group. Adult rats were operated by sham operation and collateral vessels from the caudal mesenteric artery was ligated with silk ties, and the superior mesenteric artery was occluded with a microvascular clip for half an hour and was reperfused for 2 h [6].

Group 3: ambroxol pretreated intestinal IR group (35 mg ambroxol was given into the rat vein 5 min before the surgical operation) [7].

Group 4: ambroxol pretreated intestinal IR group (70 mg ambroxol was given into the rat vein 5 min before the surgical operation).

Group 5: ambroxol pretreated intestinal IR group (140 mg ambroxol was given into the rat vein 5 min before the surgical operation) [8].

Biochemical parameters

The blood samples will be collected from retrobulbar vessels [9]. Samples were centrifuged at 2000 rpm for 15 min for separation of serum and stored at −20°C for biochemical analysis.

Measurement of blood urea

Urea in the sample is hydrolyzed enzymatically into ammonia and carbon dioxide. Ammonia ions formed reacts with salicylate and hypochlorite (NaClO) in the presence of the catalyst nitroprusside, to form green indophenols. The intensity of the color formed is proportional to the urea concentration in the sample [10].

Measurement of blood creatinine

The assay is based on the reaction of creatinine with sodium picrate.

Creatinine reacts with alkaline picrate forming a red complex.

The time interval chosen for measurement avoids interference from other serum constituents. The intensity of the color formed is proportional to creatinine concentration in the plasma [11].

Measurement of serum troponin-I activity

Serum troponin-I activity was determined according to the method used by Bodor [12].

Measurement of malondialdehyde in the heart and kidney

Thiobarbituric acid reacts with malondialdehyde (MDA) in acidic medium at a temperature of 90°C for 30 min to form thiobarbituric acid reactive product. The absorbance of the resultant pink product can be measured at 534 nm [13].

Histopathology of the heart, kidney, and intestine

After functional studies were completed, heart, kidney, and intestine were removed and put into a buffered 4% formaline fixation solution and processed with paraffin wax for histopathological examination. Sections (5 µm) were stained with hematoxylin and eosin [14].

Statistical analysis

In the statistical comparison between the different groups, the significance of difference was tested using analysis of variance test (F value): used to compare the mean of more than two groups of quantitative data using multiple comparison post-hoc test (least significant difference). A P value less than 0.05 was considered statistically significant, whereas more than 0.05 was statistically insignificant. P value less than 0.01 was considered highly significant.


  Results Top


Serum level of cardiac troponin-I changes

In intestinal IR nontreated group there was a statistically significant increase (P<0.05) in the serum troponin-I level compared with the control group. Pretreatment of intestinal IR group with ambroxol resulted in significant reduction (P<0.05) in serum troponin-I level compared with intestinal the IR nontreated group but it was still at a significant higher level (P<0.05) if compared with the control group ([Figure 1]).
Figure 1 Effect of ambroxol on troponine.

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Serum level of urea changes

In intestinal IR nontreated group, there was a statistically significant increase (P<0.05) in the serum urea level compared with the control group. Pretreatment of intestinal IR group with ambroxol resulted in a significant reduction (P<0.05) in serum urea level compared with intestinal IR nontreated group, but it was still at a significant higher level (P<0.05) if compared with the control group ([Figure 2]).
Figure 2 Effect of ambroxol on urea.

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Serum level of creatinine changes

In intestinal IR nontreated group there was a statistically significant increase (P<0.05) in serum creatinine level compared with the control group. Pretreatment of intestinal IR group with ambroxol resulted in significant reduction (P<0.05) in serum urea level compared with intestinal IR nontreated group, but it was still at a significant higher level (P<0.05) if compared with the control group ([Figure 3]).
Figure 3 Effect of ambroxol on creatinine.

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Level of malondialdehyde changes in the heart

In the intestinal IR nontreated group, there was a statistically significant increase (P<0.05) in the MDA level in the heart compared with the control group. Pretreatment of intestinal IR group with ambroxol resulted in a significant reduction (P<0.05) in the MDA level in the heart compared with the intestinal IR nontreated group, but it was still at a significant higher level (P<0.05) if compared with the control group ([Figure 4]).
Figure 4 Effect of ambroxol on MDA heart.

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Level of malondialdehyde changes in the kidney

In intestinal IR nontreated group there was a statistically significant increase (P<0.05) in the MDA level in the kidney compared with the control group. Pretreatment of intestinal IR group with ambroxol resulted in a significant reduction (P<0.05) in the MDA level in the kidney compared with the intestinal IR nontreated group, but it was still at a significant higher level (P<0.05) if compared with the control group ([Figure 5] and [Table 1]).
Figure 5 Effect of ambroxol on MDA kidney.

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Table 1 Effect of prophylactic therapy with multiple doses of ambroxol 5 min before experimentally induced intestinal ischemia–reperfusion on different parameters among the studied groups

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Histopathological examination

Heart

Control group: showed normal cardiac architecture composed of cardiac muscle fibers and normal blood vessels (healthy myocardium) ([Figure 6]).
Figure 6 Cut section in heart control group.

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Intestinal IR nontreated group: showed acute inflammatory cell infiltration and congestion ([Figure 7]).
Figure 7 Cut section in heart non treated group.

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Ambroxol-treated group (35 mg/kg): showed a decrease in inflammatory cells and congestion ([Figure 8]).
Figure 8 Cut section in heart ambroxol treated group 35 mglKG.

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Ambroxol-treated group (70 mg/kg): showed a decrease in inflammatory cells and congestion in degree more than the ambroxol-treated group (35 mg/kg) ([Figure 9]).
Figure 9 Cut section in heart ambroxol treated group 70 mglKG.

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Ambroxol-treated group (140 mg/kg): showed a decrease in inflammatory cells and congestion in degree more than the ambroxol-treated group (70 mg/kg) ([Figure 10]).
Figure 10 Cut section in heart ambroxol treated group 140 mglKG.

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Kidney

Control group: showed regular morphology of renal parenchyma with well-designated glomeruli and tubules with no infiltration of inflammatory cells ([Figure 11]).
Figure 11 Cut section in kidney control group.

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Intestinal IR nontreated group: showed a marked degree of inflammatory cells infiltration and tubular cell vacuolation ([Figure 12]).
Figure 12 Cut section in kidney non treated group.

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Intestinal IR ambroxol-treated group (35 mg/kg): showed a decrease in inflammatory cells and congestion ([Figure 13]).
Figure 13 Cut section in kidney ambroxol treated group 35 mglKG.

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Intestinal IR ambroxol-treated group (70 mg/kg): showed decrease in inflammatory cells and congestion in degree more than the ambroxol-treated group (35 mg/kg) ([Figure 14]).
Figure 14 Cut section in kidney ambroxol treated group 70 mglKG.

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Intestinal IR ambroxol-treated group (140 mg/kg): showed a decrease in inflammatory cells and congestion in degree more than the ambroxol-treated group (70 mg/kg)([Figure 15]).
Figure 15 Cut section in kidney ambroxol treated group 140 mglKG.

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Intestine

Control group: showed normal intestinal architecture composed of normal intestinal villi and goblet cells ([Figure 16]).
Figure 16 Cut section in intestine control group.

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Intestinal IR nontreated group: showed loss of villi, presence of hemorrhage, edema in the submucosa, and inflammatory infiltrate ([Figure 17]).
Figure 17 Cut section in intestine non treated group.

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Ambroxol-treated group (35 mg/kg): showed loss of villi, presence of hemorrhage, edema in the submucosa, and inflammatory infiltrate (no improvement) ([Figure 18]).
Figure 18 Cut section in intestine ambroxol treated group 35 mglKG.

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Ambroxol-treated group (70 mg/kg): showed loss of villi, presence of hemorrhage, edema in the submucosa, and inflammatory infiltrate (no improvement) ([Figure 19]).
Figure 19 Cut section in intestine ambroxol treated group 70 mglKG.

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Ambroxol-treated group (140 mg/kg): showed loss of villi, presence of hemorrhage, edema in the submucosa, and inflammatory infiltrate (no improvement) ([Figure 20]).
Figure 20 Cut section in intestine ambroxol treated group 140 mglKG.

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  Discussion Top


Oxidative stress in organisms appears when the balance between oxidants and antioxidants is disrupted due to either inadequate antioxidant activity or excessive accumulation of the reactive oxygen species, or both, leading to oxidative damage [15].

The data of the present work has shown that intestinal ischemia for half an hour and perfusion for 2 h caused significant elevation in the serum level of cardiac troponin 1 urea, creatinine, and significant elevation in the MDA level in cardiac, renal tissues.

Histopathological examination has shown cardiac, renal, and intestinal alteration in the form of inflammatory cells infiltration and congestion.

These results are in agreement with He et al. [16] who reported that oxidative stress is involved in local and systemic lesions in intestinal IR, because the accumulation of reactive oxygen species can lead to protein oxidation, lipid peroxidation, and DNA damage.

Results obtained have shown that intestinal IR caused significant affection in cardiac functions in the form of elevation of cardiac troponin 1 in serum; this is consistent with Horton and White [17] who reported that intestinal IR is an oxidative stress process leading to cardiac contractile injury in the form of fall in the left ventricular pressure and a rightward shift in the left ventricular function curves, and a decreased responsiveness to perfusate Ca2+.

Results obtained have shown that intestinal IR caused a significant elevation in the serum levels of urea and creatinine; this is consistent with Alexandropoulos et al. [18], who reported that intestinal IR lead to renal tissue injury with an elevation of serum levels of urea and creatinine and histopathological alteration in the renal tissue.

Results obtained have shown that intestinal IR caused significant elevation in remote tissue MDA as the heart and kidney; this is consistent with Kazantzidou et al. [19], who reported that intestinal IR caused significant oxidative injury in rat renal parenchyma which consisted of severe alterations observed in the subcellular renal structures associated with a significant increase in renal MDA levels.

Histopathological examination of the heart has shown that intestinal IR resulted in cardiac tissue injury in the form of multiple congested capillaries between fibers and mononuclear infiltrate among the muscle fibers; this is consistent with Zickri et al. [20], who reported that intestinal IR induced cardiac muscle degenerative changes.

Histopathological examination of the kidney has shown that intestinal IR resulted in renal tissue injury in the form of marked degree of inflammatory cells infiltration and tubular cell vacuolation; this is consistent with Stringa et al. [21], who reported that intestinal IR is an inflammatory process leading to local and remote organ injury in the form of histological alteration in the liver (sinusoidal congestion and hepatic vacuolization) and the kidney (acute tubular necrosis and hydropic degeneration).

Histopathological examination of the intestine has shown that intestinal IR resulted in intestinal tissue injury in the form of loss of villi, presence of hemorrhage, edema in the submucosal layer, and inflammatory infiltrate; this is in agreement with Ben Shahar et al. [22], who reported that intestinal IR causes intestinal apoptotic cell death and mucosal cell damage.

Results obtained have shown that the use of ambroxol in three different doses in intestinal IR lead to an improvement in the abnormal levels of cardiac function (cardiac troponine 1); this is in agreement with Czech et al. [23], who showed that treatment with ambroxol reduces the doxorubicin-induced oxidative stress in hearts and lungs of mice and significantly attenuated the DOX-elicited rise in the end products of lipid peroxidation and H2O2 activity in hearts and lungs.

Results obtained have shown that the use of ambroxol in three different doses in intestinal IR lead to an improvement in the abnormal levels of urea and creatinine (kidney function) in the serum; this is in agreement with Liu et al. [24], who showed that ambroxol is effective in reducing cardiopulmonary bypass-induced renal injury in children undergoing repair of ventricular septal defect through normalization of abnormal kidney function (serum level of urea).

Results obtained have shown that the use of ambroxol in three different doses (3 570 140 mg/kg) in intestinal IR lead to an improvement in the abnormal MDA level in remote tissues (heart and kidney); this is in agreement with Tian et al. [25], who reported that ambroxol could influence the status of oxidative stress in the lung and alleviate lung injury induced by paraquat and improve abnormal levels of MDA in blood.

Results obtained have shown that the use of ambroxol in three different doses in intestinal IR lead to improvement of remote tissue (kidney and heart) inflammatory and oxidative stress affection as seen in histopathological examination; this is consistent with Ottonello et al. [26], who proved that ambroxol can limit the excessive recruitment of neutrophils in inflamed bronchopulmonary tissue and inhibit the production of cytokines.

Results obtained have shown that the antioxidant and anti-inflammatory effect of ambroxol increased by increasing the dose; this is consistent with Jiang et al. [8], who proved that ambroxol alleviates hepatic IR injury in dose–effect relationship.

Results obtained have shown that the use of ambroxol in three different doses in intestinal IR cannot improve the abnormalities in intestinal tissue histology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20]
 
 
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