Formation and breakdown of adenosine in the heart : investigations on myocardial purine metabolismen

Adenosine, a strong coronary vasodilator, is a breakdown product of the myocardial high-energy phosphate ATP. ATP serves as the direct energy source for contraction of the heart. Chapter 1 of this thesis gives a general introduction on contractility dependent ATP-breakdown, the ATP-generating metabolism of the heart and the mechanism which leads to adenosine formation. The applications of purine biochemistry to cardiovascular research are summarized. The in vitro characteristics of other enzymes of purine metabolism (AMP-deaminase and S-adenosylhomocysteine hydrolase) are reported. Additional perfusion studies with specific inhibitors suggest a significant contribution by these enzymes to myocardial purine formation during normoxia (Appendix Papers II and IV) . Several lines of evidence suggest that the purines released from isolated rat hearts are in part degradation products of IMP or GMP instead of AMP. This appears to be especially so during normoxia. If hypoxanthine or inosine are added to the myocardial perfusate, they are slowly incorporated into the ATP-pool of the heart. The incorporation rate is increased after a previous ischemic period and can be further stimulated by simultaneous infusion of ribose. Evidence is presented that increased adenosine formation is directly related to increased formation of AMP (e.g., from ATP). The old hypothesis that adenosine is constantly produced at a high rate and nearly simultaneously reincorporated into AMP appears to be unrealistic. The results suggest an even tighter coupling of adenosine and purine release to the myocardial energy state than had already been assumed. A minor disbalance between ATP-breakdown and ATP-production will lead to increased adenosine and purine release and will eventually lead to significant loss of ATP and myocardial function. Some of the experiments point to ways of breaking through this vicious circle by defining conditions for enhanced myocardial ATP-repletion and possible restoration of function during reperfusion