Alteration of glycogen and glucose metabolism in ischaemic and post-ischaemic working rat hearts by adenosine A1 receptor stimulation.
1. Cardioprotection by adenosine A1 receptor activation limits infarct size and improves post-ischaemic mechanical function. The mechanisms responsible are unclear but may involve alterations in myocardial glucose metabolism. 2. Since glycogen is an important source of glucose during ischaemia, we examined the effects of N6-cyclohexyladenosine (CHA), an A1 receptor agonist, on glycogen and glucose metabolism during ischaemia as well as reperfusion. 3. Isolated working rat hearts were perfused with Krebs-Henseleit solution containing dual-labelled 5-3H and 14C glucose and palmitate as energy substrates. Rates of glycolysis and glucose oxidation were measured directly from the production of 3H2O and 14CO2. Glycogen turnover was measured from the rate of change of [5-3H and 14C]glucosyl units in total myocardial glycogen. 4. Following low-flow (0.5 ml min-1) ischaemia (60 min) and reperfusion (30 min), left ventricular minute work (LV work) recovered to 22% of pre-ischaemic values. CHA (0.5 microM) improved the recovery of LV work 2 fold. 5. CHA altered glycogen turnover in post-ischaemic hearts by stimulating glycogen synthesis while having no effects on glycogen degradation. CHA also partially inhibited glycolysis. These changes accelerated the recovery of glycogen in CHA-treated hearts and reduced proton production. 6. During ischaemia, CHA had no measurable effect on glycogen turnover or glucose metabolism. Glycogen phosphorylase activity, which was elevated after ischaemia, was inhibited by CHA, possibly in response to CHA-induced inhibition of AMP-activated protein kinase activity. 7. These results indicate that CHA-induced cardioprotection is associated with alterations of glycogen turnover during reperfusion as well as improved metabolic coupling of glycolysis to glucose oxidation.
Fraser
H
H
Department of Pharmacology, Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Lopaschuk
G D
GD
Clanachan
A S
AS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D006005:Phosphorylases / Q000378:metabolism; D011522:Protons; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D016276:Ventricular Function
D010710:Phosphates; D011522:Protons; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D019308:Palmitic Acid; C027513:N(6)-cyclohexyladenosine; D006003:Glycogen; D006005:Phosphorylases; D006006:Glycogen Synthase; D000263:Adenylate Kinase; D005947:Glucose; D000241:Adenosine