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...

Background-Nitric oxide (NO) causes vasodilation by stimulation of guanylate cyclase in vascular smooth muscle to produce cGMP. The resultant vasodilator effect is regulated by a family of cGMP phosphodiesterases (PDEs). Sildenafil, a selective inhibitor of PDE5 used for treatment of erectile dysfunction, has been found to cause relaxation of isolated epicardial coronary artery segments. The present study examined the effects of sildenafil on coronary blood flow and hemodynamics during exercise in normal and ischemic heart. Methods and Results-In chronically instrumented normal dogs, sildenafil 2 mg/kg PO caused a slight but significant increase in left anterior descending (LAD) coronary blood flow during resting conditions, with a nonsignificant trend toward increased coronary flow during treadmill exercise. Exercise in the presence of LAD stenosis that decreased distal coronary pressure to 57Ϯ2 mm Hg reduced LAD flow during exercise from 69Ϯ8 to 41Ϯ7 mL/min (PϽ0.05), with hypoperfusion most severe in the subendocardium. At the same distal coronary pressure, sildenafil increased LAD flow in the ischemic region to 50Ϯ11 mL/min (PϽ0.05). Increase in ischemic region blood flow produced by sildenafil was uniform across the LV wall, given that no change occurred in the transmural distribution of perfusion. Conclusions-Inhibition of PDE5 with sildenafil caused vasodilation of coronary resistance vessels with an increase of blood flow into an ischemic myocardial region during exercise in the presence of coronary artery stenosis. (Circulation.

Background —Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. Methods and Results —We measured the oxidation products of NO (nitrate+nitrite=NO x ) in aortic and coronary sinus plasma using chemiluminescence to assess NO x production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 μg/min) and bradykinin (3.0 μg/min). No coronary NO x production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO x production measured. In contrast, coronary production of NO x was significantly increased in response to endothelium-dependent agonists. Conclusions —Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.