Phentolamine prevents the adverse effects of adenosine on glycolysis and mechanical function in isolated working rat hearts subjected to antecedent ischemia

Adenosine inhibits glycolysis from exogenous glucose, reduces proton produc tion and enhances post ischemic left ventricular minute work (LV work) foll owing ischemia in isolated working rat hearts perfused with glucose and fat ty acids. In hearts partially depleted of glycogen by antecedent ischemic s tress (AIS)-two cycles of ischemia (10 min) and reperfusion (5 min)-adenosi ne stimulates rather than inhibits glycolysis, increases proton production and worsens recovery of post-ischemic LV work. We determined if the switch in adenosine effect on glycolysis and recovery of LV work following ischemi a in hearts subject to AIS was due to the reduction in glycogen content per se or because of alpha-adrenoceptor stimulation, One series of hearts unde rwent a 35-min period of substrate-free Langendorff perfusion (substrate-fr ee glycogen depletion: SFGD) and a second series of hearts was subjected to AIS. Both series of hearts had a similar glycogen content (similar to 70 m u mol/g dry wt) prior to drug treatment. In SFGD hearts perfused aerobicall y, adenosine (500 mu M) inhibited glycolysis from exogenous glucose and red uced proton production. In SFGD hearts reperfused after prolonged ischemia, adenosine exerted similar effects on glucose metabolism and enhanced recov ery of postischemic LV work (87.2 +/- 2.2% of preischemic values) relative to untreated hearts (25.9 +/- 13.3% of preischemic values). In AIS hearts p erfused aerobically or subject to ischemia and reperfusion, phentolamine (1 mu M) given in combination with adenosine, prevented adenosine-induced sti mulation of glycolysis from exogenous glucose and reduced calculated proton production from glucose. Recoveries of post-ischemic LV work in AIS hearts for untreated, adenosine, phentolamine and adenosine/phentolamine groups w ere 34.4 +/- 11.4%. 8.6 +/- 3.9%, 16.3 +/- 13.5% and 73.2 +/- 13.1% respect ively, of preischemic values. Glycogen depletion in the absence of ischemia does not switch the effect of adenosine From inhibition to stimulation of glycolysis or alter the cardioprotective properties of adenosine in hearts subject to ischemia and reperfusion. The detrimental switch in the metaboli c and cardioprotective effects of adenosine, in hearts subject to AIS, can be prevented by phentolamine, an alpha-adrenoceptor antagonist, These data support the concept that modulation of glucose metabolism is an important f actor in the mechanical functional recovery of the post-ischemic heart. (C) 2000 Academic Press.