The role of nitric oxide (NO) in the regulation of 02 consumption was studied in chronically instrumented conscious dogs. A specific NO synthesis inhibitor, nitro-L-arginine (NLA, 30 mg/kg IV), significantly increased mean arterial pressure from 100±4 to 134±5 mm Hg (mean±SEM) and total peripheral resistance by 157±16% and reduced cardiac output by 47±3% and heart rate by 34±6% after 120 minutes. Changes in arterial blood gases were not observed. There were significant changes in Po2 (-14±2 mm Hg), 02 saturation (-21±2%), the percentage of hemoglobin as oxyhemoglobin (-21±2%), and 02 content (-3.0±0.9 vol%) and a significant increase in percent reduced hemoglobin (21±1%) in mixed venous blood, associated with an increase in 02 extraction (5.1±0.2 vol%) (all P<.01). 02 consumption was increased from 124± 6 to 155 ±9 mL/min (P<.05). Methoxamine, titrated to have hemodynamic effects similar to those of NLA (eg, itric oxide (NO) formed during the metabolism N of L-arginine1-3 has been identified as an important endothelium-derived relaxing factor (EDRF), which is released from the endothelium and results in vascular smooth muscle relaxation through a cGMP-dependent mechanism.3-5 NO is also found in the central nervous system, where it may mediate some forms of interneuronal communication.6 In addition, NO has been found in activated macrophages, where it is responsible for cytotoxicity and its production is induced after cytokine stimulation.7-9 The mechanism for cytotoxicity of activated macrophages is dependent on NO production, which has multiple actions including inhibition of mitochondrial respiration in target cells. Three mitochondrial enzymes are affected by NO: (1) aconitase in the tricarboxylic acid cycle and (2) NADH+-ubiquinone oxidoreductase and (3) succinateubiquinone oxidoreductase, which are part of complex I and complex II of the mitochondrial electron transport chain.9-11It was recently reported that in cultured rat hepatocytes and rat aortic smooth muscle cells, NO production induced by cytokines results in significant inhibition of aerobic energy metabolism through the inhibition of the mitochondrial enzymes.12-14 Because all observations of the effects of NO on respiratory function previous to these findings were examined in vitro and involved the induction of NO synthase, which is associated with the production of relatively large local concentrations of Received January 28, 1994; accepted August 24, 1994 (Circ Res. 1994;75:1086-1095 Key Words * constitutive nitric oxide synthase * cardiac output * nitro-L-arginine * mitochondrial function . oxygen extraction * barbiturates NO and with pathophysiological conditions, we wondered whether the constitutive pathways of NO production could regulate tissue metabolism under normal physiological conditions. Therefore, the present study addressed the question whether tissue 02 consumption is modulated physiologically in vivo by NO produced by the constitutive NO synthase.In the present study, nitro-L-arginine (NLA), a specific NO synthesis i...

(1) ATP contents progressively decreased during heart failure as a result of a loss of the total purine pool. The loss of purines may be due to inhibition of de novo purine synthesis. (2) Loss of creatine is an early marker of heart failure and may serve as a compensatory mechanism minimizing the reduction of the total purine pool in the failing heart.

This study determined the changes in NO production from the coronary circulation of the conscious dog during exercise. The role of endogenous NO as it relates to coronary flow, myocardial work, and metabolism was also studied. Mongrel dogs were chronically instrumented for measurements of coronary blood flow (CBF), ventricular and aortic pressure, and ventricular diameter, with catheters in the aorta and coronary sinus. Acute exercise (5 minutes at 3.6, 5.9, and 9.1 mph) was performed, and hemodynamic measurements and blood samples were taken at each exercise level. Nitro-L-arginine (NLA, 35 mg/kg IV) was given to block NO synthesis, and the exercise was repeated. Blood samples were analyzed for oxygen, plasma nitrate/nitrite (an index of NO), lactate, glucose, and free fatty acid (FFA) levels. Acute exercise caused significant elevations in NO production by the coronary circulation (46 +/- 23, 129 +/- 44, and 63 +/- 32 nmol/min at each speed respectively, P < .05). After NLA, there was no measurable NO production at rest or during exercise. Blockade of NO synthesis resulted in elevations in myocardial oxygen consumption and reductions in myocardial FFA consumption for comparable levels of CBF and cardiac work. The metabolic changes after NLA occurred in the absence of alterations in myocardial lactate or glucose consumptions. NO production by the coronary circulation is increased with exercise and blocked by NLA. The absence of NO in the coronary circulation during exercise does not affect levels of CBF, because it shifts the relationship between cardiac work and myocardial oxygen consumption, suggesting that endogenous NO modulates myocardial metabolism.

The mechanism responsible for the regulation of cardiac function by endogenous nitric oxide (NO) remains unclear. In this investigation, O2 consumption by freshly isolated myocardial muscle segments from the left ventricular free wall of canine hearts was quantified by a Clark-type O2 electrode at 37 degrees C. S-nitroso-N-acetylpenicillamine (SNAP, 9 +/- 3% to 50 +/- 8%), bradykinin (BK, 14 +/- 3% to 30 +/- 5%), or carbachol (CCh, 15 +/- 4% to 29 +/- 4%) significantly attenuated tissue O2 consumption at doses of 10(-7) to 10(-4) mol/L (mean +/- SE, P < .05). The effects of BK and CCh, but not SNAP, were blocked by 10(-4) mol/L NG-nitro-L-arginine, consistent with both BK and CCh stimulating NO biosynthesis and with SNAP decomposing to release NO, respectively. Similar doses of 8-Br-cGMP caused a respiratory inhibition, but to a lesser extent (9 +/- 2% to 14 +/- 6%). A mitochondrial uncoupler, 2,4-dinitrophenol (at 1 mmol/L), blocked the effects of 8-Br-cGMP, but not those of SNAP, BK, or CCh, suggesting that the major site of action of NO is on mitochondrial electron transport. Myocardial muscle from dogs with pacing-induced heart failure had a basal O2 consumption rate of 251 +/- 21 nmol.min-1.g-1, which was 54% higher than the rate seen in muscle from normal healthy canine hearts. The inhibitory effects of BK and CCh on O2 consumption were not observed in failing cardiac tissue, but SNAP showed an unaltered inhibitory effect. Therefore, our results indicate that NO released from microvascular endothelium by BK, stimulation of muscarinic receptors, and perhaps flow velocity may play an important physiological role in the control of cardiac mitochondrial respiration, and the loss of this regulatory function may contribute to the development of heart failure.