Rapid Turnover of the AMP-Adenosine Metabolic Cycle in the Guinea Pig Heart

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The intracellular flux rate through adenosine kinase (adenosine→AMP) in the well-oxygenated heart was investigated, and the relation of the AMP-adenosine metabolic cycle (AMP⇄adenosine) to transmethylation (S-adenosylhomocysteine [SAHI→adenosine) and coronary flow was determined. Adenosine kinase was blocked in isolated guinea pig hearts by infusion of iodotubercidin in the presence of the adenosine deaminase blocker erythro-9-(2-hydroxy-3-nonyl)adenine (5 μmol/L). lodotubercidin (1 nmol/L to 4 μmol/L) caused graded increases in venous effluent concentrations of adenosine, from 8±3 to 145±32 nmol/L (mean±SEM, n=3), and in coronary flow, which increased to maximal levels. Flow increases were completely abolished by adenosine deaminase (5 to 10 U/mL). Interstitial adenosine concentrations, estimated using a mathematical model, increased from 22 nmol/L during control conditions to 420 nmol/L during maximal vasodilation. The possibility that iodotubercidin caused increased venous adenosine by interfering with myocardial energy metabolism was ruled out in separate 31P nuclear magnetic resonance experiments. To estimate total normoxic myocardial production of adenosine (AMP→adenosine←SAH), the time course of coronary venous adenosine release was measured during maximal inhibition of adenosine kinase with 30 μmol/L iodotubercidin. Adenosine release increased more than 15-fold over baseline, reaching a new steady-state value of 3.4±0.3 nmol min−1 g−1 (n=5) after 4 minutes. In parallel experiments, the relative roles of AMP hydrolysis and transmethylation (SAH hydrolysis) were determined, using adenosine dialdehyde (10 μmol/L) to block SAH hydrolase. In these experiments, adenosine release increased to similar levels of 3.4±0.5 nmol min−1 g−1 (n=6) during inhibition of adenosine deaminase and adenosine kinase. It is concluded that (1) maximal increases in coronary flow are elicited by increases in interstitial adenosine concentration to approximately 400 nmol/L, (2) more than 90% of the adenosine produced in the heart is normally rephosphorylated to AMP without escaping into the venous effluent, (3) AMP hydrolysis is the dominant pathway for cardiac adenosine production under normoxic conditions, and (4) the high rate of adenosine salvage is due to rapid turnover of a metabolic cycle between AMP and adenosine. Rapid cycling may serve to amplify the relative importance of AMP hydrolysis over transmethylation in controlling cytosolic adenosine concentrations.

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