Increased sensitivity of mitochondrial respiration to inhibition by nitricoxide in cardiac hypertrophy

Cardiac hypertrophy is a significant risk factor for the development of con gestive heart failure (CHF). Mitochondrial defects are reported in CHF, but no consistent mitochondrial alterations have yet been identified in hypert rophy. In this study selective metabolic inhibitors were used to determine thresholds for respiratory inhibition and to reveal novel mitochondrial def ects in hypertrophy. Cardiac hypertrophy was produced in rats by aortic ban ding. Mitochondria were isolated from left ventricular tissue and the effec ts of inhibiting respiratory complexes I and IV on mitochondrial oxygen con sumption were measured. At 8 weeks post-surgery 65 +/- 2% complex IV inhibi tion was required to inhibit respiration half maximally in control mitochon dria. In contrast, only 52 +/- 6% complex IV inhibition was required to inh ibit respiration half maximally in mitochondria from hypertrophied hearts ( P = 0.046). This effect persisted at 22 weeks post-surgery and was accompan ied by a significant upregulation of inducible nitric oxide synthase (iNOS, 3.0 +/- 0.7-fold, P = 0.006). We conclude that respiration is more sensiti ve to complex IV inhibition in hypertrophy. Nitric oxide is a well document ed inhibitor of complex IV, and thus the combination of increased NO. from iNOS and an increased sensitivity to inhibition of one of its targets could result in a bioenergetic defect in hypertrophy that may be a harbinger of CHF. (C) 2000 Academic Press.