Adenosine production and its role in protection against ischemic and reperfusion injury of the myocardium

Abstract

Adenosine exerts cardioprotective effects on the ischemic myocardium. A flexibly mounted microdialysis apparatus was used to measure the concentration of interstitial adenosine and to assess the activity of ecto-5′-nucleotidase (a key enzyme responsible for adenosine production) in in vivo rat hearts. The level of adenosine during adenosine 5′-adenosine monophosphate (AMP) perfusion serves as an index of the activity of ecto-5′-nucleotidase in the tissue. Endogenous norepinephrine (NE) activates α1-adrenoceptors to lead to the activation of protein kinase C (PKC), which, in turn, activates ecto-5′-nucleotidase via phosphorylation, thereby enhancing the production of interstitial adenosine. Histamine-induced release of NE activates PKC, which increases ecto-5′-nucleotidase activity and augments release of adenosine. Nicorandil, a hybrid of an ATP sensitive K+ (KATP) channel opener and nitrate, increases the level of interstitial adenosine via cGMP-mediated activation of ecto-5′-nucleotidase. Opening of cardiac KATP channels may cause hydroxyl radical (·OH) generation. Nitric oxide (NO) facilitates the production of interstitial adenosine, via activation of ecto-5′-nucleotidase. However, singlet oxygen (1O2) is a very powerful oxidant that causes inactivation of ecto-5′-nucleotidase to result in a decrease in the concentration of adenosine in rat heart. Adenosine plays an important role as a modulator of ischemic reperfusion injury. The production and action of adenosine are intimately linked to the release of NE.