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Sensitivity of mechanical and metabolic functions to changes in coronary perfusion: A metabolic basis of
1Institute for Cellular Therapeutics, University of Louisville, USA. askenasy+@andrew.cmu.edu
Abstract:
Experimental evidence indicates a metabolic basis of contraction-perfusion coupling during an increase in cardiac work load. This study aims to characterize adjustment of myocardial energy metabolism in response to acute low flow ischemia (LFI), and to determine its involvement in perfusion-contraction coupling. Intracellular parameters were measured in isolated rat hearts by NMR spectroscopy and biochemical methods during 30 min of graded LFI and reperfusion as compared to continuous perfusion (control). Oxygen pressure was set to reach maximal oxygen extraction at 70% coronary flow rate (CFR), therefore oxygen limitation was proportional to coronary underperfusion. At 69, 38 and 10% CFR left ventricular pressures decreased to 71, 43 and 25% of pre-ischemic values respectively (P<0.005 v 97% in control) without an increase in diastolic tone, and recovered to 92+/-3% after 30 min of reperfusion. Despite hydrolysis of high energy phosphates and cellular acidification, ADP concentrations were stable in underperfused hearts. At 69, 38 and 10% CFR, cytosolic phosphorylation potentials (PP) decreased from 74+/-10 m M(-1)during pre-ischemia to 40+/-6, 25+/-4 and 14+/-4 m M(-1)respectively (P<0.05 v 63+/-9 m M(-1)in control), and lactate efflux increased to 256+/-18, 386+/-22 and 490+/-43 micromol /gdw respectively (P<0.005 v 186+/-22 micromol/gdw in control). Glycogen contents decreased (P<0.005 v control) and accounted for 27-30% of lactate efflux. These results indicate: (a) proportionate depression of contraction force and glycogen contents, and increased glucose uptake and anaerobic energy production in the underperfused myocardium. Coordinated modulation of these parameters attributes cytosolic PP a regulatory function; (b) resetting of cytosolic PP to lower levels mediates perfusion-contraction coupling during graded LFI. The data are consistent with the concept that glycolytic energy production improves myocardial tolerance to ischemia.