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Essay: Investigate the effect of Saroglitazar on myocardial ischemia

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  • Published: 22 October 2015*
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Ischemic heart disease is the leading cause of the death worldwide, according to the third monitoring report of the World Health Organization cause 12 million death throughout the world each year. Approximately 1.5 million cases of myocardial infarction occur annually in the United States; yearly incidence rate is approximately 600 cases/1, 00,000 people.[1]
Myocardial infarction is death of the myocardium tissue; extent and location of infarction depend upon the degree of ischemic burden, the availability of coronary collateral blood flow, the rapidity of reperfusion and location of the afflicted coronary artery.
Oxidative stress refers to the cytopathologic consequences of an imbalance between the production of free radicals and the defense system. Oxidative stress plays an important role in cardiomyocytes (CMs) cell death by the way of apoptosis or necrosis. Reactive oxygen spices as H2O2 and OH’ are known to cause apoptosis.[2]
High dose of H2O2 induce necrosis, whereas low dose cause apoptosis in a variety of cell types including CMs.[3] NO’ also act as an inducer of apoptosis in monocytes, macrophages, and CMs.[4,5] TNF-?? also induces CMs apoptosis in the heart, this effect is mediated by oxidative stress.[6] Reactive oxygen spices (ROS) appear to be the principle mediators of CM dysfunction in various pathologic conditions,[7] causing both apoptosis and necrosis. CM death induced by oxidative stress is associated with the standard structural and biochemical changes indicative of apoptosis, distinct from necrosis. Excessive ROS may derive from intracellular sources such as mitochondrial dysfunction or may be secreted by infiltrating neutrophil during the inflammatory response to the ischemic insult.[8] In many case, evidence suggest that increase in numbers of ROS induces apoptosis.[9]
Isoproterenol (ISO), a ??-adrenergic agonist, has been found to cause severe stress in the myocardium resulting in infarct like necrosis of the heart muscle.[10] Some of the
mechanisms proposed to explain ISO induced damage to cardiac myocytes includes hypoxia due to myocardial hyperactivity, and coronary hypotension, calcium overload, depletion of energy reserve and excessive production of free radicals resulting from oxidative metabolism of catecholamine.[11]
Research effort in recent years have provided increasing evidence that PPAR represent major regulators of this inflammatory response; PPAR activation could be shown to restrict inflammation and exert multiple beneficial effects against ischemia injury Consequently, pharmacological agents targeting PPAR have been suggested as potential therapeutics for the treatment of I/R.[5,6] PPAR activation has multiple anti-inflammatory properties in shock, sepsis, myocardial ischemia, and multiple organ failure. This fact has to be taken in consideration when a potential therapeutically use of PPAR agonists in the treatment of myocardial ischemia, and therefore in present study we wasing to check effect of Saroglitazar against myocardial ischemia.
PPAR?? agonists were found to protect tissue injury against ischemia by inhibiting inflammatory reaction, improving endothelial function, reducing oxidative stress and calcium overload.[24]
PPAR?? agonists also effective in reducing lactate accumulation, ventricular arrhythmias, creatine kinase-MB release and restoring energy production in MI/R.[25]
Saroglitazar is a thiazolidinedione with PPAR??/?? agonist activity.[4]
Therefore we hypothesized that Saroglitazar (PPAR??/?? agonist) might be effective against MI injury.
1.2: AIM
‘ To investigate the effect of Saroglitazar on myocardial ischemia in rats
‘ To measure ECG findings
‘ To study the effect of Saroglitazar against myocardial ischemia by evaluating infracts size and area at risk.
‘ To examine histopathological change
‘ To assess the cardiac injury by estimating cardiac injury markers.
‘ To study the effect of Saroglitazar on antioxidant enzymes induced by MI
‘ To estimate the level of inflammatory response

2.1. Myocardial infarction
2.1.1. Introduction
Myocardial infarction is the common presentation of the ischemic heart disease. It occurs when myocardial ischemia surpasses the critical threshold level for an extended time resulting in irreversible myocardial cell damage. Although clinical care is improved, public awareness is raised and health innovations are widely used, myocardial infarction still remains the leading cause of death worldwide. According to the World Health Organization it will be the major cause of death in the world by the year 2020. An increase in myocardial oxygen demand relative to the available myocardial supply or an acute decrease in myocardial oxygen delivery can participate acute myocardial ischemic injury. Episodes of ischemia that last more than 30 minutes usually cause myocardial infarction. The involved area can be divided into three zones 1) zone of infarction 2) zone of injury 3) zone of ischemia. Death of muscle (infarction) causes due to absence of depolarization current from dead tissue and opposing current from other parts of heart. The infarction may be limited to the interior of the myocardium (subendocardial MI) or to a visceral layer of the pericardium or may extend through the full thickness of the myocardial wall (transmural MI). The most common cause of acute myocardial infarction (AMI) is atherosclerosis of coronary arteries, which narrows the coronary lumen and reduce myocardial blood supply.
Patient at higher risk for suffering an AMI are those with a prior history of AMI, CAD, or malignant arrhythmias. Modifiable factors include cigarette smoking, diabetes mellitus, hyperlipidemia, hypertension, obesity and physical inactivity and non modifiable factors includes increase age, male sex and family history, both risk factors increase the risk of MI. Participating factors for AMI include vasospasm, physical or emotional stress, hemorrhage, trauma, hypoglycemia, respiratory failure, hypersensitivity reaction, exogenous sympathomimetics or other vasoactive substances. The characteristic pattern of ischemic injury involve fluid and electrolyte
alteration with loss of K+, Mg+2 and accumulation of water, Na+, Cl-, H+ and Ca+2. Cytoplasmic organaeller and cellular swelling with plasma membrane blabbing and migration and clumping of nuclear chromatin. Several mechanisms of myocardial tissue injury, occurring during and after diminution of myocardial perfusion, are as follows.
2.1.2. Depletion of high energy phosphates
To sustain the continuous contractile function, the myocardium is absolutely dependent on aerobic metabolism for the production of energy in the form of adenosine triphosphate (ATP), because myocyte contain very limited reserve stores of high-energy phosphates. During normoxia, ATP is produced in the mitochondria by oxidative phosphorylation. Under physiological conditions there is hardly any break down of the high-energy phosphates to purines, as the purine-producing enzymes are scarcely active. However, during oxygen and substrate deprivation, breakdown of high-energy phosphates become predominant, a disorder that is accompanied by cellular and sub cellular alterations in the cardiac myocyte.[17] ST segment elevation myocardial infarction is usually caused by persistent thrombotic occlusion of a coronary artery resulting in sustained reductions in coronary blood flow and myocardial oxygen availability. Occasionally, increases in myocardial oxygen demand above the ability of a stenotic coronary artery to delivery oxygen cause MI, often Non ST segment elevation myocardial infarction. Such increases in oxygen demand occur in some patients with CAD who have severe systemic arterial hypertension, sustained tachycardia, or both. Alternatively, sustained reductions in myocardial oxygen delivery associated with severe systemic arterial hypotension may lead to MI, again usually Non ST segment elevation myocardial infarction. Approximately 30% of patients with Non ST segment elevation myocardial infarction have an occlusive thrombus in the infarct-related artery.[18]
Furthermore, in response to oxygen deprivation, adenosine can be released from the myocytes. It may enter the extracellular space where it has multiple effects. Its protective role is manifested by vasodilatation and by effects to decrease myocardial oxygen demand (i.e. negative ionotropism, chrono-tropism and dromotropism).During

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