Effects of carvedilol on isolated heart mitochondria: Evidence for a protonophoretic mechanism

Carvedilol ({1-[carbazolyl-(4)-oxyl-3-[2-methoxyphenoxyethyl)amino]-propano l-(2)}) is a novel compound used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension, and myocardial inf arction, Carvedilol was also shown to protect cardiac mitochondria from oxi dative stress events. Because mitochondria are the main suppliers of ATP fo r cardiac muscle work, a study of the effects of carvedilol in mitochondria l bioenergetics is necessary to fully understand the basis of its protectiv e role in myocardial energetics. In this work we show that carvedilol acts as an uncoupler of oxidative phosphorylation, decreasing mitochondrial elec tric potential (Delta Psi) by a weak protonophoretic mechanism. Theoretical studies were carried out to determine the relevance of conformation and pr oton affinity of the protonable amino side-chain group in the proton-shuttl ing activity across the inner mitochondrial membrane. BM910228, a hydroxyla ted metabolite of carvedilol, was also studied for comparison with the pare nt compound, Implications for the protective role of carvedilol in heart mi tochondrial bioenergetics are discussed. (C) 2000 Academic Press.