The oxidative pentose phosphate pathway in the heart: regulation, physiological significance, and clinical...

The capacity of the oxidative pentose phosphate pathway (PPP) in the heart is small, since the activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and rate-limiting enzyme, is very low. Basically, two mechanisms are involved in the regulation of this pathway. Under normal conditions, G-6-PD is inhibited by NADPH. This can immediately be overcome in the isolated perfused rat heart by increasing the oxidized glutathione and by elevating the NADP+/NADPH ratio. Apart from this rapid control mechanism, there exists a long-term regulation which involves the synthesis of G-6-PD. All catecholamines that were administered stimulated the activity of myocardial G-6-PD in a time- and dose-dependent manner. This stimulation was due to increased new synthesis of enzyme protein, since the G-6-PDmRNA was specifically enhanced. As a consequence of the stimulation of the oxidative PPP, the available pool of 5-phosphoribosyl-1-pyrophosphate (PRPP) was elevated which serves as an important precursor substrate for purine and pyrimidine nucleotide synthesis. The limiting step in the oxidative PPP can be bypassed by ribose which leads to an elevation of the cardiac PRPP pool. The decline in the ATP that is induced in many pathophysiological conditions can be attenuated or even entirely prevented by i.v. infusion of ribose. In some experimental in vivo rat models such as in the overloaded and catecholamine-stimulated heart and in the non-ischemic region of the infarcted heart, the normalization of the metabolic situation was accompanied by an improvement of global heart function. Ribose application has been shown to be beneficial in several clinical disease states such as myoadenylate deaminase deficiency and McArdle's disease. Moreover, ribose facilitated thallium-201 redistribution and markedly improved the detection of reversible ischemic injury of the pig and human heart.