Abstract-Our objective was to determine the precise role of endothelial nitric oxide synthase (eNOS) as a modulator of cardiac O 2 consumption and to further examine the role of nitric oxide (NO) consumption in tissues taken from iNOS (Ϫ/Ϫ) (Ϫ28Ϯ4%), wild-type eNOS (ϩ/ϩ) (Ϫ22Ϯ4%), and heterozygous eNOS(ϩ/Ϫ) (Ϫ22Ϯ5%) but not homozygous eNOS (Ϫ/Ϫ) (Ϫ3Ϯ4%) mice. Responses to bradykinin in iNOS (Ϫ/Ϫ) and both wild-type and heterozygous eNOS mice were attenuated after NOS blockade with N-nitro-L-arginine methyl ester (L-NAME) (Ϫ2Ϯ5%, Ϫ3Ϯ2%, and Ϫ6Ϯ5%, respectively, PϽ0.05). In contrast, S-nitroso-N-acetyl-penicillamine (SNAP, 10Ϫ4 mol/L), which releases NO spontaneously, induced decreases in myocardial O 2 consumption in all groups of mice, and such responses were not affected by L-NAME. In addition, pretreatment with bacterial endotoxin elicited a reduction in basal O 2 consumption in tissues taken from normal but not iNOS (Ϫ/Ϫ)-deficient mice. Our results indicate that the pivotal role of eNOS in the control of myocardial O 2 consumption and modulation of mitochondrial respiration by NO may have an important role in pathological conditions such as endotoxemia in which the production of NO is altered. . Their initial observations demonstrated that activated mouse peritoneal macrophages severely inhibited O 2 consumption in numerous tumor cell lines obtained from different tissues and animal species in cultures by an unknown mechanism. Evidence now suggests that the macrophage-induced cytotoxic effect on mitochondrial metabolism is NO related. 2,3 NO inhibits respiration by nitrosylating the iron-sulfur centers of aconitase, complexes I and II of the electron transport chain, and through a very potent reversible alteration in the activity of cytochrome c oxidase. 4 -6 Recently, we and others have provided direct evidence to suggest that under physiological conditions NO plays a modulatory role on mitochondrial respiration and tissue O 2 consumption. For instance, L-arginine analogues, which are nonspecific inhibitors of the 3 isoforms of nitric oxide synthase (NOS), 7 increase O 2 consumption in whole body, 8 heart, skeletal muscle, and kidney both in vivo 9 -12 and in vitro. [12][13][14] We have interpreted our previous studies to suggest that endothelial nitric oxide synthase (eNOS), the most highly expressed isoform of NOS in vascular tissue under physiological conditions, is responsible for the control of tissue O 2 consumption by NO. However, we have yet to determine which isoform of NOS regulates mitochondrial O 2 consumption, because almost all cells are capable of expressing all 3 different NOS isoforms. Studies of the effects of bacterial endotoxins have attributed a substantial role for inducible nitric oxide synthase (iNOS) in the development of shock and perhaps other pathological states. To address the role of NO in both physiological and pathophysiological states in the control of mitochondrial respiration, we used tissues from mice deficient in iNOS and eNOS and 3 additional groups, ie, control C57B...
Inhibition of NO synthesis has recently been shown to increase oxygen extraction in vivo, and NO has been proposed to play a significant role in the regulation of oxygen consumption by both skeletal and cardiac muscle in vivo and in vitro. It was our aim to determine whether NO also has such a role in the kidney, a tissue with a relatively low basal oxygen extraction. In chronically instrumented conscious dogs, administration of an inhibitor of NO synthase, nitro-L-arginine (NLA, 30 mg/kg i.v.), caused a maintained increase in mean arterial pressure and renal vascular resistance and a decrease in heart rate (all P<0.05). At 60 minutes, urine flow rate and glomerular flow rate decreased by 44+/-12% and 45+/-7%, respectively; moreover, the amount of sodium reabsorbed fell from 16+/-1.7 to 8.5+/-1.1 mmol/min (all P<0.05). At this time, oxygen uptake and extraction increased markedly by 115+/-37% and 102+/-34%, respectively (P<0.05). Oxygen consumption also significantly increased from 4.5+/-0.6 to 7.1+/-0.9 mL O2/min. Most important, the ratio of oxygen consumption to sodium reabsorbed increased dramatically from 0.33+/-0.07 to 0.75+/-0.11 mL O2/mmol Na+ (P<0.05), suggesting a reduction in renal efficiency for transporting sodium. In vitro, both a NO-donating agent and the NO synthase-stimulating agonist bradykinin significantly decreased both cortical and medullary renal oxygen consumption. In conclusion, NO plays a role in maintaining a balance between oxygen consumption and sodium reabsorption, the major ATP-consuming process in the kidney, in conscious dogs, and NO can inhibit mitochondrial oxygen consumption in canine renal slices in vitro.
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