Adenosine production and its interaction with protection of ischemic and reperfusion injury of the myocardium.
Adenosine exerts cardioprotective effects on the ischemic myocardium. A flexibly mounted microdialysis probe 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 perfusion of adenosine 5'-adenosine monophosphate (AMP) was given as an index of the activity of ecto-5'-nucleotidase in the tissue. Endogenous norepinephrine (NE) activates both alpha(1)-adrenoceptors and protein kinase C (PKC), which, in turn, activates ecto-5'-nucleotidase via phosphorylation thereby enhancing the production of interstitial adenosine. Histamine-release NE activates PKC, which increased ecto-5'-nucleotidase activity and augmented release of adenosine. Opening of cardiac ATP sensitive K(+) (K(ATP)) channels may cause hydroxyl radical (.OH) generation through NE release. Lysophosphatidylcholine (LPC), an endogenous amphiphiphilic lipid metabolite, also increases the concentration of interstitial adenosine in rat hearts, through the PKC-mediated activation of endogenous ecto-5'-nucleotidase. Nitric oxide (NO) facilitates the production of interstitial adenosine, via guanosine 3',5'-cyclic monophosphate (cGMP)-mediated activation of ecto-5'-nucleotidase as another pathway. These mechanisms play an important role in high sensitivity of the cardiac adenosine system. Adenosine plays an important role as a modulator of ischemic reperfusion injury, and that the production and mechanism of action of adenosine are linked with NE release.
Obata
Toshio
T
Department of Pharmacology and Therapeutics, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. tobata@oita-med.ac.jp
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000241:Adenosine / Q000096:biosynthesis*; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006801:Humans; D054086:KATP Channels; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D017551:Microdialysis; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats
D018528:ATP-Binding Cassette Transporters; D005609:Free Radicals; D054086:KATP Channels; D008244:Lysophosphatidylcholines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D009569:Nitric Oxide; D015720:5'-Nucleotidase; D006152:Cyclic GMP; D000241:Adenosine