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.
Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
Alberto
A
Boveris
Gabriela
G
D'Amico
Silvia
S
Lores-Arnaiz
Lidia E
LE
Costa
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