الفهرس 
Left ventricular dysfunction (LVD)Only 14 pages are availabe for public view
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Abstract
Summary and conclusion
Left ventricular dysfunction is a clinical syndrome that develops in response to an insult resulting in a decline in the pumping capacity of the heart. This insult can be either ischemia or hypertension that damage cardiac tissue and even environmental insults that disturb the systemic circulation in general. Once the cardiac damage occurs, compensatory neurohormonal mechanisms that are activated which are initially able to compensate for the depressed myocardial function. However, their long-term activation has deleterious effects on cardiac structure and performance, leading to myocardial fibrosis and decompensation which results finally into arrhythmia and sudden cardiac death.
Consequently, new strategies must develop to inhibit the inflammatory and fibrotic reactions in the late stage ventricular dysfunction for better control of fibrosis in cardiac patients.
Perindopril is one of the ACE inhibitors that has a key role in treatment of many cardiovascular disorders especially interrupting the viscous cycle of sympathetic activation that leads to heart failure.
In the last two decades, increasing interest about potential therapeutic cardioprotective effects of melatonin has established. It exhibits anti- oxidant, antihypertensive and anti-inflammatory effects in many organs including heart and it is now considered as a promising agent to counteract the cardiac fibrosis by regulating all phases of fibrotic reactions.
Aim of the work:
The present study was designed to investigate the possible beneficial effect of melatonin (10mg/kg/day) when combined with perindopril (5mg/kg/day) on cardiac hemodynamics, myocardial damage, oxidative stress, inflammation and fibrosis, together with investigating the histopathological changes in an animal model of left ventricular dysfunction induced by doxorubicin in (L-NAME) hypertensive rats.
Study design:
30 male albino rats were divided randomly into 5 groups, 6 rats each:
11- Control group (naïve) animals: received standard rat chow and tap water for 8 weeks.
12- L-NAME/doxorubicin untreated rats: L-NAME (40mg/kg/day) for 8 weeks by daily oral gavage and doxorubicin (2.5 mg/kg/twice per week) for the last 3 weeks by intraperitoneal injection.
13- Perindopril treated rats: L-NAME/doxorubicin intoxicated rats treated with perindopril (5mg/kg/day) for the last 3 weeks (Louise et al., 2005) by daily oral gavage.
14- Melatonin treated rats: L-NAME/doxorubicin intoxicated rats treated with melatonin (10mg /kg/day) for last 3 weeks (Simko et al., 2014b) by daily oral gavage.
15- Perindopril/Melatonin treated rats: L-NAME/ doxorubicin intoxicated rats with a combination of perindopril (5mg/kg/day) and melatonin (10mg/kg/day) for the last 3weeks by daily oral gavage.
The duration of the whole study lasted for 8 weeks. Drugs were administered daily from the 6thweek.
The following parameters were measured:
I: Hemodynamic parameters:
1) Systolic Blood Pressure (SBP).
2) Left ventricular end diastolic pressure (LVEDP).
3) Left ventricular dp/dtmax (indicator for cardiac contractility).
II: Biochemical parameters:
9) Cardiac enzymes (Creatine kinase – MB).
10) Cardiac Oxidative stress markers (SOD - MDA).
11) Cardiac Tumor necrosis factor-alpha (TNF-α).
12) Cardiac Transforming growth factor –beta (TGF-β).
III: Histopathological changes in heart tissues stained with Hematoxylin and eosin and Masson’s Trichrome.
Results:
I-Hemodynamic results:
Administration of L-NAME for 5 weeks increased the systolic blood pressure significantly (p<0.05) in comparison to baseline while SBP was decreased significantly (p<0.05) after administration of doxorubicin. At the end of the study, concomitant use of L-NAME and doxorubicin exhibited significant (p<0.05) decrease in LV dp/dt max and significant (p<0.05) increase in LVEDP compared to normal control group.
After 8 weeks all treated groups produced significant decrease (P<0.05) in SBP compared with their corresponding at the 5th week.
In addition, both melatonin and perindopril when administered alone increased LV dp/dt max significantly (p<0.05) and decreased LVEDP but only perindopril decreased it significantly (p<0.05) in comparison to L-NAME/ DOX untreated rats.
Combination of melatonin and perindoporil showed significant decrease (p<0.05) in SBP after 8 weeks of the study compared to the corresponding SBP at the 5th weeks. Besides, it showed significant (p<0.05) increase in LV dp/dt max , and significant (p<0.05) decrease in LVEDP compared to L-NAME/ DOX untreated rats and perindopril alone.
II-Biochemical results:
At the end of the study, administration of L-NAME for 8 weeks with concomitant use of doxorubicin in the last 3 weeks exhibited significant (p<0.05) increase in CK-MB, MDA, TNF-α and TGF-β and significant (p<0.05) decrease in SOD compared to normal control group .
Both melatonin and perindopril when administered alone produced significant (p<0.05) decrease in CK-MB, MDA, TNF-α and TGF-β, also both increased SOD significantly (p<0.05) compared to L-NAME/ DOX untreated rats. Combination of melatonin and perindoporil showed significant (p<0.05) decrease in MDA, TNF-α and TGF-β, and significant (p<0.05) increase in SOD compared to L-NAME/ DOX untreated rats, and perindopril alone. The combination also showed significant (p<0.05) decrease in CK-MB compared to L-NAME/ DOX untreated rats but it insignificantly (p>0.05) decreased it in comparison to perindopril alone.
III-Histopathological results:
Stained cardiac sections of L-NAME/ DOX untreated rats showed extravasated blood cells between cardiac muscle fibers and some fibers showed pyknotic nuclei while others were disrupted, fragmented and widely separated. They also showed statistical significant increase in cardiac percentage area of collagen fibers compared to control rats.
Stained cardiac sections of rats treated with both perindopril and melatonin revealed few areas with congested interstitial blood capillaries between muscle fibers with apparent decrease of inflammatory cell infiltration with significant reduction in collagen percentage area compared to L-NAME/ DOX untreated rats. Furthermore, Perindopril /Melatonin treated group, stained sections were nearly similar to the control group. The cardiac muscle fibers were slightly disorganized with mild spacing and extravasated blood cells. This was accompanied with statistical significant decrease in the cardiac percentage area of collagen fibers compared to L-NAME/ DOX untreated and perindopril treated rats.