Sequential changes of energy metabolism and mitochondrial function in myocardial infarction induced by isoproterenol in rats: a long-term and integrative study

Abstract

Acute myocardial infarction is the second cause of mortality in most countries, therefore, it is important to know the evolution and sequence of the physiological and biochemical changes involved in this pathology. This study attempts to integrate these changes and to correlate them in a long-term model (96 h) of isoproterenol-induced myocardial cell damage in the rat. We achieved an infarct-like damage in the apex region of the left ventricle, occurring 12-24 h after isoproterenol administration. The lesion was defined by histological criteria, continuous telemetric ECG recordings, and the increase in serum marker enzymes, specific for myocardial damage. A distinction is made among preinfarction, infarction, and postinfarction. Three minutes after drug administration, there was a 60% increase in heart rate and a lowering of blood pressure, resulting possibly in a functional ischemia. Ultrastructural changes and mitochondrial swelling were evident from the first hour of treatment, but functional alterations in isolated mitochondria, such as decreases in oxygen consumption, respiratory quotient, ATP synthesis, and membrane potential, were noticed only 6 h after drug administration and lasted until 72 h later. Mitochondrial proteins decreased after 3 h of treatment, reaching almost a 50% diminution, which was maintained during the whole study. An energy imbalance, reflected by a decrease in energy charge and in the creatine phosphate/creatine ratio, was observed after 30 min of treatment; however, ATP and total adenine nucleotides diminished clearly only after 3 h of treatment. All these alterations reached a maximum at the onset of infarction and were accompanied by damage to the myocardial function, drastically decreasing left ventricular pressure and shortening the atrioventricular interval. During postinfarction, a partial recovery of energy charge, creatine phosphate/creatine ratio, membrane potential, and myocardial function occurred, but not of mitochondrial oxygen consumption, rate of ATP synthesis, total adenine nucleotides, or mitochondrial proteins. Interesting correlations of the sequential changes in heart and mitochondrial functions with energy metabolism were obtained at different stages of the isoproterenol-induced cardiotoxicity. These correlations could be useful to study and understand the cellular events involved in this pathology.

Mechanisms of isoproterenol‐induced cardiac mitochondrial damage: protective actions of melatonin

“…ISO, a β ‐adrenergic agonist, produces gross and microscopic infarcts in rat heart similar to those seen during myocardial ischemia in humans . Several studies have investigated the molecular and cellular mechanisms of ISO‐induced cell injury of the myocardium . We have recently demonstrated that ISO‐induced myocardial damage to rat heart in vivo involves the generation of oxidative stress .…”

“…Generation of oxidative stress leading to mitochondr‐ial dysfunction is one of the principal factors behind the pathophysiology of several diseases including cardiovascular disorders, Alzheimer's disease, autoimmune disorders, and cancer . Involvement of oxidative stress in the initiation and progression of ischemic heart disease has been recognized in experimental as well as in human situations . ISO, a β ‐adrenergic agonist, produces gross and microscopic infarcts in rat heart similar to those seen during myocardial ischemia in humans .…”

“…Involvement of oxidative stress in the initiation and progression of ischemic heart disease has been recognized in experimental as well as in human situations . ISO, a β ‐adrenergic agonist, produces gross and microscopic infarcts in rat heart similar to those seen during myocardial ischemia in humans . Several studies have investigated the molecular and cellular mechanisms of ISO‐induced cell injury of the myocardium .…”

Phytochemical screening and evaluation of cardioprotective activity of ethanolic extract of Ocimum basilicum L. (basil) against isoproterenol induced myocardial infarction in rats

“…Isoproterenol is a synthetic β-adernoceptor agonist that its subcutaneous injection induces myocardial infarction in rats [11] and results in irreversible cellular damage and ultimately infarct-like necrosis [12,13]. The acute phase of myocardial necrosis and dysfunction induced by isoproterenol mimics changes in blood pressure, heart rate, electrocardiogram (ECG), and left ventricular dysfunction similar to that occurs in patients with myocardial infarction.…”

Insulin-Like Growth Factor-1 (IGF-1) Reduces ischemic changes and increases circulating angiogenic factors in experimentally - induced myocardial infarction in rats

“…The mechanism of isoproterenol-induced myocardial injury includes cytosolic calcium overload, lipid peroxide generation and pro-coagulant activity [15,16]. The pathological process of isoproterenol-induced myocardial damage is characterized by patchy areas of myocardial ischemia.…”