EXTRACELLULAR ADENOSINE LEVELS AND CELLULAR-ENERGY METABOLISM IN ISCHEMICALLY PRECONDITIONED RAT-HEART

Objective: Microdialysis and P-31-NMR spectroscopy were used to test o pposing hypotheses that ischemic preconditioning inhibits adenine nucl eotide degradation and purine efflux, or that preconditioning activate s cardiovascular adenosine formation to provide enhanced cardioprotect ion. Methods: 31P-NMR spectra and matching interstitial fluid (ISF) or venous effluent samples were obtained from Langendorff perfused rat h earts. Control hearts (n=9) underwent 30 min of global normothermic is chemia and 30 min reperfusion. Preconditioned hearts (n=6) were subjec ted to a 5 min ischemic episode and 10 min reflow prior to 30 min isch emia and 30 min reperfusion. Effects of repetitive ischemia-reperfusio n (3x5 min ischemic episodes) on adenosine levels and energy metabolis m were also assessed (n=8). Results: Preconditioning improved post-isc hemic recovery of heart rate x left ventricular developed pressure (71 +/-5 vs 43+/-8%, P<0.05) and end-diastolic pressure (14+/-3 vs 29+/-4 mmHg, P<0.05) compared with control hearts, respectively. Precondition ing did not alter intracellular ATP, phosphocreatine (PCr), inorganic phosphate (P-i), H+ or free Mg2+ during global ischemia, but improved recoveries of PCr, P-i, and Delta G(ATP) on reperfusion. ISF adenosine increased more than 20-fold during 30 min ischemia. The 5 min precond itioning episode increased ISF adenosine 3-fold, and reduced ISF adeno sine and inosine during subsequent prolonged ischemia by up to 75%. Ve nous purine levels during reperfusion were also reduced by preconditio ning. Accumulation of adenosine in ISF and venous effluent during repe titive ischemia was progressively reduced despite comparable changes i n substrate for adenosine formation via 5'-nucleotidase (5'-AMP), and in allosteric modulators of this enzyme (Mg2+, H+, P-i, ADP, ATP). Con clusions: (i) Ischemic preconditioning reduces interstitial and vascul ar adenosine levels during ischemia-reperfusion, (ii) reduced ISF aden osine during ischemia is not due to reduced ischemic depletion of aden ine nucleotides in preconditioned rat hearts, (iii) preconditioning ma y inhibit adenosine formation via 5'-nucleotidase in ischemic rat hear ts, and (iv) improved functional recovery with preconditioning is unre lated to metabolic/bioenergetic changes during the ischemic insult, bu t may be related to improved post-ischemic recovery of [P-i] and Delta G(ATP) in this model. (C) 1998 Elsevier Science B.V. All rights reser ved.