Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments.
Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, Po(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 <or= 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 approximately 49% of total cellular NO production in sea level rats and for approximately 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.
Zaobornyj
Tamara
T
Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina. tamaraz@ffyb.uba.ar
Valdez
Laura B
LB
Iglesias
Darío E
DE
Gasco
Manuel
M
Gonzales
Gustavo F
GF
Boveris
Alberto
A
D000222:Adaptation, Physiological / Q000187:drug effects* / Q000502:physiology; D000531:Altitude; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001835:Body Weight; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006400:Hematocrit; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009929:Organ Size; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C478189:respiratory complex II; D009569:Nitric Oxide; D001120:Arginine; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D019331:NG-Nitroarginine Methyl Ester