Superoxide ( [Formula: see text] ) has been implicated in the pathogenesis of many human diseases including
hypertension. Mitochondria-targeted
superoxide scavenger
mitoTEMPO reduces blood pressure; however, the structure-functional relationships in
antihypertensive effect of mitochondria-targeted nitroxides remain unclear. The nitroxides are known to undergo bioreduction into
hydroxylamine derivatives which reacts with [Formula: see text] with much lower rate. The nitroxides of
pyrrolidine series (proxyls) are much more resistant to bioreduction compared to
TEMPOL derivatives suggesting that mitochondria-targeted proxyls can be effective
antioxidants with
antihypertensive activity. In this work we have designed and studied two new
pyrrolidine mitochondria targeted nitroxides: 3-[2-(triphenyphosphonio)acetamido]- and 3-[2-(triphenyphosphonio) acetamidomethyl]-2,2,5,5-tetramethylpyrrolidine-1-oxyl (mCP2) and (mCP1). These new mitochondria targeted nitroxides have 3- to 7-fold lower rate constants of the reaction with O2(-•) compared with
mitoTEMPO; however, the cellular bioreduction of mCP1 and mCP2 was 3- and 2-fold slower. As a consequence incubation with cells afforded much higher intracellular concentration of mCP1 and mCP2 nitroxides compared to
mitoTEMPO nitroxide. This has compensated for the difference in the rate of O2(-•) scavenging and all nitroxides similarly protected mitochondrial respiration in H2O2 treated endothelial cells. Treatment of hypertensive mice with mCP1 and mCP2 (1.4mg/kg/day) after onset of
angiotensin II-induced
hypertension significantly reduced blood pressure to 133±5mmHg and 129±6mmHg compared to 163±5mmHg in mice infused with
angiotensin II alone. mCP1 and mCP2 reduced vascular O2(-•) and prevented decrease of endothelial
nitric oxide production. These data indicate that resistance to bioreduction play significant role in
antioxidant activity of nitroxides. Studies of
nitroxide analogs such as mCP1 and mCP2 may help in optimization of chemical structure of mitochondria-targeted nitroxides for improved efficacy and pharmacokinetics of these drugs in treatment of
hypertension and many other conditions including
atherosclerosis, diabetes and degenerative
neurological disorders in which mitochondrial oxidative stress seems to play a role.