Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 296; no. 6; pp. H1741 - H1747
• Main Authors: Zaobornyj, Tamara, Valdez, Laura B, Iglesias, Dario E, Gasco, Manuel, Gonzales, Gustavo F, Boveris, Alberto
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2009
• Subjects: Adaptation, Physiological - drug effects; Adaptation, Physiological - physiology; Altitude; Animals; Arginine - pharmacology; Body Weight; Cells; Electron Transport Complex I - metabolism; Electron Transport Complex II - metabolism; Electron Transport Complex III - metabolism; Electron Transport Complex IV - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Heart; Heart - physiology; Hematocrit; Hypertrophy, Right Ventricular - drug therapy; Hypertrophy, Right Ventricular - metabolism; Hypertrophy, Right Ventricular - physiopathology; Male; Mitochondria - enzymology; Myocardium - metabolism; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Organ Size; Phosphodiesterase Inhibitors - pharmacology; Piperazines - pharmacology; Purines - pharmacology; Rats; Rats, Sprague-Dawley; Rodents; Sildenafil Citrate; Sulfones - pharmacology; Cerro de Pasco Peru
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00422.2008

1 Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina; and 2 Facultad de Ciencias y Filosofía, Departamento de Ciencias Biológicas y Fisiológicas, Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima, Peru Submitted 22 April 2008 ; accepted in final form 1 April 2009 Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, P O 2 = 12.2 kPa) for up to 84 days showed a physiological adaptive response with decreased body weight gain (15%), increased right ventricle weight (100%), and increased hematocrit (40%) compared with sea level animals. These classical parameters of adaptation to high altitude were accompanied by an increase in heart mitochondrial enzymes: complexes I-III activity by 34% and mitochondrial nitric oxide synthase (mtNOS) activity and expression by >75%. The hyperbolic increase for mtNOS activity during adaptation to high altitude was similar to the observed pattern for hematocrit. Hematocrit and mtNOS activity mean values correlated linearly ( r 2 = 0.75, P 0.05). Chronic treatment for 28 days with sildenafil (50 mg·kg –1 ·day –1 ) decreased the response of mtNOS to high altitude by 25%. Conversely, N G -nitro- L -arginine methyl ester treatment (8.3 mg·kg –1 ·day –1 ) increased such response by 40%, whereas L -arginine treatment (106 mg·kg –1 ·day –1 ) had no effect. Nitric oxide (NO) production by mtNOS accounts for 49% of total cellular NO production in sea level rats and for 54% in rats exposed to high altitude for 84 days. It is concluded that mtNOS is a substantial source of cardiac NO, a factor in the adaptive response to sustained heart hypoxia that is susceptible to be modified by pharmacological treatments. mitochondrial nitric oxide synthase activity; mitochondrial nitric oxide synthase expression; mitochondrial respiratory complexes; hematocrit; nitro- L -arginine methyl ester Address for reprint requests and other correspondence: T. Zaobornyj, Fisicoquímica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, C1113AAD, Buenos Aires, Argentina (e-mail: tamaraz{at}ffyb.uba.ar )