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 (H(2)O(2)) production (from 30% in control rats to 52%). Calculated heart intramitochondrial NO and H(2)O(2) steady-state concentrations were increased 66% and 20%, respectively, by enalapril treatment. Signaling pathways dependent on mitochondrial NO and H(2)O(2) may account for the beneficial effects of enalapril in aging mammals.
Boveris
Alberto
A
Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
D'Amico
Gabriela
G
Lores-Arnaiz
Silvia
S
Costa
Lidia E
LE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013053:Spectrophotometry; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D014867:Water / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D006454:Hemoglobins; D014867:Water; D009569:Nitric Oxide; D004656:Enalapril; D008706:Methemoglobin; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D010100:Oxygen