Metabolism of 5-amino-4-imidazolecarboxamide riboside in cardiac and skeletal muscle. Effects on purine nucleotide synthesis

Depletion of purine nucleotide pools is postulated to play a role in cardiac and skeletal muscle dysfunction. Increasing the rate of purine nucleotide synthesis in these cells offers a potential mechanism for reversing this pathological process. Eight millimoles of 5-amino-4-imidazolecarboxamide riboside (AICAriboside) were administered to each of 7 dogs over 40 min, and myocardial and skeletal muscle biopsies were obtained for the determination of AICAriboside, its metabolites, and purine nucleotide pools. Plasma AICAriboside concentration reached a peak of 336 ± 26 μM at the end of infusion. Myocardial and skeletal muscle content of AICAriboside rose progressively throughout the infusion. 5-Amino-4-imidazolecarboxamide ribotide (AICAR) content reached a maximum of 0.188 ± 0.034 and 0.032 ± 0.013 μM/g, wet weight, in cardiac and skeletal muscle, respectively. IMP content rose 3-4-fold (cardiac) and 6-7-fold (skeletal) in both muscle types with AICAriboside infusion. The adenine nucleotide pool of myocardium increased 10% (p<0.005) with AICAriboside infusion. Inosine and hypoxanthine content of skeletal muscle rose significantly dirng AICAriboside infusion. Adenosine content of cardiac and skeletal muscle was unchanged. Serum urate concentration rose 3.7-fold at the end of AICAriboside infusion. A potential explanation for the diversion of most of the newly synthesized IMP into the catabolic pathway, i.e. inosine, hypoxanthine, and urate, was found in a kinetic study of adenylosuccinate lyase (EC 4.3.2.2). AICAR inhibited the cardiac and skeletal muscle enzyme with K(i) values of 4.5 ± 1.7 and 7.6 ± 3.2 μM, respectively. Peak intracellular concentrations of AICAR in cardiac and skeletal muscle were 180- and 18-fold greater than the K(i) values for the respective enzymes. It is postulated that the accumulation of AICAR inhibits adenylosuccinate lyase and diverts the bulk of newly synthesized IMP into the catabolic pathway.