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Protecting the Myocardium From Ischemic Injury^*

A Critical Role for ₁-Adrenoreceptors?

^* From the Department of Medicine, Southampton General Hospital, Southampton, UK.

Correspondence to: Sundeep Salvi, MD, DNB, PhD, University Medicine, Level D Centre Block, Southampton General Hospital, Southampton SO16 6YD, UK; e-mail: sundeepsalvi{at}hotmail.com

Ischemic preconditioning (IPC) refers to the ability of short periods of ischemia to make the myocardium more resistant to a subsequent ischemic insult. It is the most powerful form of endogenous protection against myocardial infarction and has been demonstrated in all species evaluated to date. However, the cellular mechanisms that drive IPC remain poorly understood. This hypothesis describes an important role for ₁-adrenoreceptors in mediating IPC and discusses the underlying mechanisms by which this is likely achieved. ₁-Adrenoreceptors are present in the myocardium of all mammalian species, and several lines of evidence suggest that they play an important role in mediating IPC. During periods of myocardial hypoxia/ischemia, cardiomyocytes have to rely solely on anaerobic glycolysis for energy production; for this, the cells have to depend on increased glucose entry inside the cell as well as increased glycolysis. Stimulation of ₁-adrenoreceptors increases glucose transport inside the cardiomyocytes by translocating glucose transporter (GLUT)-1 and GLUT-4 from the cytoplasm to the plasma membrane, enhances glycogenolysis by activating phosphorylase kinase, increases the rate of glycolysis by activating the enzyme phosphofructokinase, reduces intracellular acidity produced during excessive glycolysis by activating the Na⁺/H⁺ exchanger, and inhibits apoptosis by increasing the levels of the antiapoptotic protein Bcl-2. Myocardial ischemia produces an increase in the expression of ₁-adrenoreceptors in cardiomyocytes, as well as increases the levels of its agonist norepinephrine by several fold. During ischemic states, upregulation of ₁-adrenoreceptors and increase in norepinephrine release could be a powerful adaptive mechanism that drives IPC. An understanding into the role of ₁-adrenoreceptors in mediating IPC could not only point to newer treatments for limiting myocardial damage during myocardial infarction or heart surgery, but could also help in avoiding the use of ₁-antagonists in patients with ischemic heart disease.

Key Words: ₁-adrenoreceptor • apoptosis • glucose • glucose transporter • ischemic preconditioning • Na⁺/H⁺ exchange • phosphofructokinase • protein kinase C

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