Increased hypoxic stress decreases AMP hydrolysis in rabbit heart

doi:10.1016/S0008-6363(99)00207-2

Cardiovascular Research 1999 44(2):333-343; doi:10.1016/S0008-6363(99)00207-2
© 1999 by European Society of Cardiology

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Increased hypoxic stress decreases AMP hydrolysis in rabbit heart

Lori A Gustafson^a^,b^,*, Coert J Zuurbier^a^,c, John E Bassett^a, Jan Paul F Barends^b, Johannes H.G.M van Beek^b, James B Bassingthwaighte^a and Keith Kroll¹^,a

^aCenter for Bioengineering, University of Washington, Seattle, WA 98195, USA
^bLaboratory for Physiology, Institute of Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
^cDepartment of Experimental Anesthesiology, Universiteit van Amsterdam, Amsterdam, The Netherlands

^* Corresponding author. Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Tel.: +31-20-444-8133; fax: +31-20-444-8255 lorig{at}physiol.med.vu.nl

Objective: AMP conversion to adenosine by cytosolic 5'-nucleotidase(5NT) or to IMP by AMP deaminase determines the degree of nucleotidedegradation, and thus ATP resynthesis, during reoxygenation.To elucidate the regulation of AMP hydrolysis during ischemia,data from ³¹P NMR spectroscopy and biochemical analyses wereintegrated via a mathematical model. Since 5NT is downregulatedduring severe underperfusion (5% flow), we tested 5NT regulationduring less severe underperfusion (10% flow) and then made theperfusate hypoxic to see if the greater stress reactivated 5NT.Methods: ³¹P NMR spectra and coronary venous effluents wereobtained from Langendorff-perfused rabbit hearts subjected totwo 30-min periods of underperfusion (10% flow); the secondperiod with or without additional hypoxia (30% O₂). Data wereanalyzed with a mathematical model describing the kinetics ofmyocardial energetics and metabolism. Results: A single 30-minperiod of 10% flow causes downregulation of AMP hydrolysis andthe data from the second period of underperfusion are best describedby lower 5NT activity, even in the presence of extra hypoxia.Thirty percent less purines appear in the venous effluent thanpredicted by the phosphoenergetics (PCr and ATP) when IMP isnot allowed to accumulate by the model, however the model indicatesthat a constant accumulation of IMP via AMP deaminase couldexplain the discrepancy between expected and measured purinesin the venous effluent. Conclusions: While AMP hydrolysis toadenosine is prominent in early ischemia and acts to preservecellular energy potential, during a second ischemic period,nucleotides are conserved by the stable inhibition of AMP hydrolysis.Furthermore, during 10% flow conditions, nucleotides are conserved,possibly via an IMP-accumulatory pathway.

KEYWORDS Adenosine; Computer modeling; Energy metabolism; Hypoxia/anoxia; Ischemia

¹ Deceased 15 July, 1997.

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