The Possible Beneficial Effect of Melatonin Co-administration to Perindopril on Left Ventricular Dysfunction Induced by Doxorubicin in Hypertensive albino Rats

Abstract

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.