Function and Production of Nitric Oxide in the Coronary Circulation of the Conscious Dog During Exercise

Abstract

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.

Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism

“…Beyond vascular smooth muscle relaxation associated with improved tissue perfusion (4)(5)(6), NO also regulates the supply of cellular energy in the face of a metabolic challenge. Thus, NO and the associated production of cGMP decrease the transport, availability through glycogenoloysis, and metabolic activation of glucose (9,10).…”

“…Thus, NO and the associated production of cGMP decrease the transport, availability through glycogenoloysis, and metabolic activation of glucose (9,10). Conversely, cGMP increases the transport and utilization of fatty acids as metabolic substrates, which are associated with a more favorable respiratory quotient (6,14). Further, cGMP shifts the balance of flux of metabolic substrates from glycolysis to oxidative phosphorylation, optimizing ATP generation (15).…”

“…Well described mechanisms control the selection of substrates and routing of their flux through anaerobic and aerobic metabolic pathways, ultimately leading to oxidative phosphorylation and the production of ATP in mitochondria (1,6,(10)(11)(12)(13)(14)39). More recently, the importance of spatially organized intracellular enzymatic networks supporting high-energy phosphoryl transfer in coupling ATP generation in mitochondria on the one hand, and ATP-consuming or -sensing processes on the other, has emerged (1).…”

“…Metabolic stress, such as ischemia, stimulates NO synthases to produce NO from arginine (3). In turn, NO regulates the supply of energy by improving the delivery of substrates and oxygen to deprived tissues (4)(5)(6), regulating the intracellular delivery of metabolic substrates (7)(8)(9)(10), selection of substrates that support metabolism (6,(10)(11)(12)(13)(14), oxidation of metabolic substrates (15), generation of ATP by improving metabolic efficiency (16), and biogenesis of mitochondria (17). Conversely, NO reduces the demand for ATP by decreasing energyconsuming cell functions, for example, by reducing the activity of the contractile apparatus in muscle cells (ref.…”

Limited Exercise Capacity in Heterozygous Manganese Superoxide Dismutase Gene–Knockout Mice

“…Blockade of NOS resulted in reductions in myocardial free fatty acid consumption for comparable levels of cardiac work. 34 The acute inhibition of NOS by nitro-L-arginine causes a switch from fatty acids to lactate and glucose utilization in the heart, which can be reversed by an NO donor. 35 Glucose uptake was increased in the mice with defects in the expression of eNOS and mice with L-NAME in a Langendorff heart preparation.…”