It was previously shown that red blood cells release ATP when blood oxygen tension decreases. ATP acts on microvascular endothelial cells to produce a retrograde conducted vasodilation (presumably via gap junctions) to the upstream arteriole. These observations form the basis for an ATP hypothesis of local metabolic control of coronary blood flow due to vasodilation in microvascular units where myocardial oxygen extraction is high. Dogs (n ϭ 10) were instrumented with catheters in the aorta and coronary sinus, and a flow transducer was placed around the circumflex coronary artery. Arterial and coronary venous plasma ATP concentrations were measured at rest and during three levels of treadmill exercise by using a luciferin-luciferase assay. During exercise, myocardial oxygen consumption increased ϳ3.2-fold, coronary blood flow increased ϳ2.7-fold, and coronary venous oxygen tension decreased from 19 to 12.9 mmHg. Coronary venous plasma ATP concentration increased significantly from 31.1 to 51.2 nM (P Ͻ 0.01) during exercise. Coronary blood flow increased linearly with coronary venous ATP concentration (P Ͻ 0.01). Coronary venous-arterial plasma ATP concentration difference increased significantly during exercise (P Ͻ 0.05). The data support the hypothesis that ATP is one of the factors controlling coronary blood flow during exercise. It has long been known that ATP is a powerful coronary dilator (8). Studies by Wolf and Berne (25) and Moir and Downs (16) demonstrated that ATP is more potent than adenosine in producing coronary vasodilation. Bergfeld and Forrester (1) observed that human red blood cells release ATP under hypoxic conditions. Ellsworth and colleagues (6, 7) demonstrated a progressive release of ATP from hamster red blood cells during declines in oxygen tension. They used oxygen tensions of ϳ35 and ϳ11 mmHg and maintained a constant pH (7.36) and carbon dioxide tension (35 mmHg). Thus ATP release from red blood cells took place during physiological declines in oxygen tension without the interaction of carbon dioxide or pH.Once released from the red blood cell, ATP acts on endothelial cell purinergic receptors (12,19). The injection of ATP inside small arterioles (5, 7, 15), outside capillaries (7), or inside venules (3) results in a retrograde conducted response that dilates the upstream feed arteriole. Duling and colleagues (9, 21) demonstrated that responses caused by several agonists are conducted along microvascular endothelial cells via gap junctions to the upstream feed arterioles. The assumption is that the conducted response due to ATP is also mediated via gap junctions. The relaxation of the feed arteriole increases oxygenated blood flow where oxygen extraction is high. Through its ability to release ATP in areas of low oxygen tension, the red blood cell may serve as a regulator of coronary blood flow during increases in myocardial oxygen consumption.The purpose of the current study was to test the ATP hypothesis in the coronary circulation during exercise. The major results of the present s...

Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O 2 Ϫ ) production, and the inhibitory effect of resistin on bradykinininduced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI2), we performed experiments with N -nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI2 production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O 2 Ϫ or interference with NO or PGI2 signaling.

These data suggest that the vagolytic effect of MEAP involves the activation of delta opiate receptors within the sinoatrial node.

Non-technical summary Activation of sympathetic nerves decreases blood flow to resting skeletal muscle, but this vasoconstrictor effect normally is blunted during exercise so that blood flow can increase to the working muscles. In rats and humans treated with nitroglycerin for 1 week, we show that overproduction of reactive oxygen species prevents the usual attenuation of sympathetic vasoconstriction in the working muscles, resulting in muscle ischaemia during exercise. Improved knowledge about the effect that reactive oxygen species has on muscle blood flow regulation may help us to better understand the decreased exercise tolerance that occurs with age as well as with chronic disease.Abstract Sympathetic vasoconstriction is normally attenuated in exercising muscle, but this functional sympatholysis is impaired in rats with hypertension or heart failure due to elevated levels of reactive oxygen species (ROS) in muscle. Whether ROS have a similar effect in the absence of cardiovascular disease or whether these findings extend to humans is not known. We therefore tested the hypothesis that chronic treatment with nitroglycerin (NTG) to induce nitrate tolerance, which is associated with excessive ROS production, impairs functional sympatholysis in healthy rats and humans. NTG treatment increased ethidium fluorescence in rat muscles and urinary F 2 -isoprostanes in humans, demonstrating oxidative stress. In vehicle-treated rats, sympathetic nerve stimulation (1 to 5 Hz) evoked decreases in femoral vascular conductance at rest (range, −30 to −63%) that were attenuated during hindlimb contraction (range, −2 to −31%; P < 0.05). In NTG-treated rats, vasoconstrictor responses were similar at rest, but were enhanced during contraction (range, −17 to −50%; P < 0.05 vs. vehicle). Infusion of the ROS scavenger tempol restored sympatholysis in these rats. In humans, reflex sympathetic activation during lower body negative pressure (LBNP) evoked decreases in muscle oxygenation in resting forearm (−12 ± 1%) that were attenuated during handgrip exercise (−3 ± 1%; P < 0.05). When these subjects became nitrate tolerant, LBNP-induced decreases in muscle oxygenation were unaffected at rest, but were enhanced during exercise (−9 ± 1%; P < 0.05 vs. before NTG). Collectively, these data indicate that functional sympatholysis is impaired in otherwise healthy nitrate-tolerant rats and humans by a mechanism probably involving muscle oxidative stress.

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