Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Abstract

Background-Endogenous nitric oxide (NO) has been reported to inhibit oxygen consumption in the normal heart, so that nonselective inhibition of NO synthase (NOS) caused an increase of myocardial oxygen consumption (MV O 2 ). Although endothelial NOS responses are depressed in congestive heart failure (CHF), inducible NOS (iNOS) may be expressed in failing myocardium. Methods and Results-This study tested the hypothesis that NOS inhibition would increase MV O 2 in the failing heart. CHF was produced in dogs by use of the rapid ventricular pacing model. ) in the normal heart, 2,3 although others found no effect 4 or a decrease in MV O 2 . 5 Three distinct NOS isoforms exist in mammalian cells: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) isoforms. 6 nNOS and eNOS are constitutively expressed in many cell types, whereas iNOS is expressed in response to infection, inflammation, or cytokine activation. Circulating and tissue levels of cytokines, including tumor necrosis factor-␣, interleukin-2, and interleukin-6, are elevated in patients with chronic heart failure, 7-9 and iNOS expression has been found in cardiac myocytes of patients with dilated cardiomyopathy, myocarditis, and ischemic heart disease, 10,11 suggesting that iNOS could be a source of NO in the failing heart. Consequently, this study was performed to determine whether selective iNOS inhibition with S-methylisothiourea (SMT) influences MV O 2 of the failing heart at rest or during exercise. The effect of SMT was compared with nonselective NOS inhibition with N G -nitro-L-arginine (L-NNA) to determine whether constitutive NOS can also modulate MV O 2 in congestive heart failure (CHF). MethodsStudies were performed in 21 adult mongrel dogs weighing 20 to 26 kg and trained to run on a treadmill. All experiments were performed in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals" as approved by the council of the American Physiological Society and with prior approval of the University of Minnesota Animal Care Committee. Surgical PreparationAnimals were anesthetized with sodium pentobarbital (30 to 35 mg/kg), intubated, and ventilated with oxygen-enriched air. A left thoracotomy was performed, and polyvinyl chloride catheters (3.0-mm OD) were inserted into the ascending aorta and the left ventricle (LV). A solid-state micromanometer (Konigsberg Instruments) was introduced into the LV at the apex. A final catheter was introduced into the right atrial appendage and advanced through the coronary sinus until the tip could be palpated at the anterior interventricular vein to allow selective sampling of blood draining the myocardium perfused by the left anterior descending coronary artery (LAD). 3 A Doppler velocity probe (Craig Hartley) was positioned on the LAD, and a silicone catheter (0.3-mm ID) was introduced into the LAD distal to the velocity probe. Catheters were tunneled to exit at the base of the neck; catheters were flushed daily Effect of SMT and L-NNA in the Normal HeartSelective iNOS inhibition was studi...

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“…In the in vivo situation, alterations in substrate preference in the failing heart, with decreased free fatty acid uptake and increased glucose utilization, could contribute to decreased oxygen utilization (10). In several previous reports pacing-induced CHF was associated with decreased MV O 2 (7,32,40), although Shen et al (37) found an increase in MV O 2 after development of CHF. These differing results may be related to differences in the duration and severity of CHF, as well as the specific protocols used to produce heart failure.…”

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