Degradation of adenine nucleotides in ischemic and reperfused rat heart

Abstract

Complete cessation of flow in isolated rat hearts for 90 min resulted in a gradual breakdown of ATP and concomitant accumulation of degradation products, such as adenosine, inosine (major break-down product), hypoxanthine, and, to a lesser extent, xanthine. After 45 min of ischemia, the content and relative composition of purines hardly changed, whereas the AMP content continued to rise. This finding points to constraints on AMP degradation and flux through the degradation pathway from adenosine to uric acid in the ischemic heart. In myocardial preparations, the cells of which were deliberately disrupted by freezing and thawing before anoxic incubation, AMP did not accumulate and was finally converted to hypoxanthine. These results indicate that compartmentalization of substrates and enzymes is responsible for the observed preferential accumulation of AMP and inosine in the ischemic heart. Inhibition of hypoxanthine degradation is explained by the absence of oxygen. Restoration of flow and oxygen supply abolished the inhibition of metabolic flux. Accumulated purines were released into the coronary effluent and, concomitantly, further metabolized. Comparison of tissue levels of hypoxanthine, xanthine, and uric acid before reperfusion and the amounts released during reperfusion indicates that in rat myocardium substantial amounts of potentially hazardous xanthine oxidase-derived reactive oxygen species are likely to be formed during the early reperfusion phase.

HIF-1α in the heart: Remodeling nucleotide metabolism

“…In tetanic exercised skeletal muscle, IMP accumulation is in direct proportion to ATP breakdown [28]. In contrast IMP accumulation is seldom seen in ischemic heart [14,29,30]. This led Manfredi et al to propose the existence of an unidentified factor in heart that limits IMP accumulation [30].…”

Ischaemia‐reperfusion induced alterations of mitochondrial function in hypertrophied rat heart

“…Ischaemia and I-R have been shown to cause an imbalance of myocardial energy supply, indicated by a degradation of adenine nucleotides, accumulation of purine byproducts, a shift from aerobic to anaerobic metabolism, and a loss of contractile properties (Van Bilsen et al 1989, Kihlstrom 1990, Bowles & Starnes 1994. There is strong evidence that the observed disturbance of heart energy metabolism is related to the irreversible damage of heart mitochondria after ischaemia or I-R, such that coupling of oxidative phosphorylation is impaired, making the myocardium incapable of performing rhythmic contraction.…”

“…In fact, mitochondria from the I-R hearts exhibited somewhat enhanced state 4 and state 3 respiration with pyruvatemalate, and respiratory control was also well maintained. These changes most likely reflected increased levels of ADP and inorganic phosphate in the postischaemic myocardium, both of which are well-known stimulants of mitochondrial respiration (Van Bilsen et al 1989. Another possible explanation may be an increased Ca# + mobilization associated with heart ischaemia (Turrens et al 1991).…”

Increased Abdominal Adiposity Exacerbates Ex-Vivo Cardiac Reperfusion Injury through Augmented Mitochondrial Oxidative Stress

“…The adenine nucleotide dephosphorylation that occurs during ischemia [29] leads to the production of two types of reactive oxygen species (ROS) during reperfusion. The first ROS becomes highly elevated, but only for a short duration at the beginning of reperfusion [30]; it is caused by oxidation of hypoxanthine by xanthine oxidase [31]. The second type of ROS becomes less increased, but for a long duration: it is caused by intracellular acidosis [32], which leads to intracellular calcium accumulation [33].…”