Enalapril increases mitochondrial nitric oxide synthase activity in heart and liver

Heart and liver mitochondria isolated from rats treated with enalapril, 3-30 mg/kg/day in the drinking water for 7-120 days, showed a time- and dose-dependent increased nitric oxide (NO) production in the range of 14-250%. Heart and liver mitochondria from control rats produced 0.69 and 0.50 nmol of NO/min/mg of protein, respectively, as determined by dual wavelength spectrophotometry (577-591 nm) following hemoglobin oxidation to methemoglobin. The response to enalapril treatment, attributed to a gene-mediated up-regulation of mitochondrial nitric oxide synthase (mtNOS) activity, was half-maximal at 5-6 days and was maintained up to 120 days. Enalapril-treated animals showed an increased mtNOS functional activity in heart mitochondria that inhibited state 3 O-2 uptake (from 22% in control rats to 43%) and increased state 4 hydrogen peroxide (H2O2) production (from 30% in control rats to 52%). Calculated heart intramitochondrial NO and H2O2 steady-state concentrations were increased 66% and 20%, respectively, by enalapril treatment. Signaling path-ways dependent on mitochondrial NO and H2O2 may account for the beneficial effects of enalapril in aging mammals.