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Carvedilol inhibits the exogenous NADH dehydrogenase in rat heart mitochondria
P J Oliveira1, D J Santos, A J Moreno
1Centro de Neurociências de Coimbra, Universidade de Coimbra, Portugal.
Insights
Carvedilol specifically inhibits external NADH dehydrogenase in rat heart mitochondria, offering a potential strategy to prevent adriamycin-induced cardiotoxicity.
Area of Science:
- Mitochondrial biochemistry
- Cardiovascular pharmacology
Background:
- Exogenous NADH dehydrogenase in mitochondria plays a role in cellular metabolism.
- Its physiological significance and specific inhibitors were previously unknown.
Purpose of the Study:
- To identify a specific inhibitor of exogenous NADH dehydrogenase.
- To investigate the role of this enzyme in mitochondrial function and potential therapeutic applications.
Main Methods:
- Enzyme kinetics studies using isolated rat heart mitochondria.
- Measurement of oxygen consumption and external medium pH.
- Utilized carvedilol as a specific inhibitor.
- Assessed membrane potential using a TPP(+) electrode.
Main Results:
- Carvedilol selectively inhibits exogenous NADH dehydrogenase (Km 13 µM) without affecting succinate or internal NADH oxidation.
- Inhibition by carvedilol (Ki 15 µM) correlates with reduced external medium alkalinization.
- Exogenous NADH does not generate mitochondrial membrane potential, confirming oxidase activity.
Conclusions:
- Carvedilol is the first specific inhibitor of organospecific exogenous NADH dehydrogenase.
- This enzyme is implicated in adriamycin-induced cardiotoxicity.
- Carvedilol may prevent cardiotoxicity in cancer patients treated with adriamycin.
Abstract:
There are several reports on the oxidation of external NADH by an exogenous NADH dehydrogenase in the outer leaflet of the inner membrane of rat heart mitochondria. Until now, however, little was known about its physiological role in cellular metabolism. The present work shows that carvedilol (¿1-[carbazolyl-(4)-oxy]-3-[2-methoxyphenoxyethyl)amino]-pro - panol-(2)¿) is a specific inhibitor of an exogenous NADH dehydrogenase in rat heart mitochondria. Carvedilol does not affect oxygen consumption linked to the oxidation of succinate and internal NADH. It is also demonstrated that the inhibition of exogenous NADH dehydrogenase by carvedilol is accompanied by the inhibition of alkalinization of the external medium. In contrast to the addition of glutamate/malate or succinate, exogenous NADH does not generate a membrane potential in rat heart mitochondria, as observed with a TPP(+) electrode. It is also demonstrated that the oxygen consumption linked to NADH oxidation is not due to permeabilized mitochondria, but to actual oxidase activity in the inner membrane. The enzyme has a K(m) for NADH of 13 microM. Carvedilol is a noncompetitive inhibitor of this external NADH dehydrogenase with a K(i) of 15 microM. Carvedilol is the first inhibitor described to this organospecific enzyme. Since this enzyme was demonstrated to play a key role in the cardiotoxicity of anticancer drugs of the anthracycline family (e.g., adriamycin), we may suggest that the administration of carvedilol to tumor patients treated with adriamycin might be of great help in the prevention of the cardioselective toxicity of this antibiotic.