Hypoxia can have profound influences on vascular tone. The balance between the local effects of hypoxia and changes in the neural control of vascular tone determines whether net vasoconstriction or vasodilatation occurs in a vascular bed (Mancia, 1975;Heistad & Abboud, 1980). Several studies indicate that this balance is dependent upon species, vascular region and the degree of hypoxia. In humans, the degree to which changes in sympathetic nerve activity mask hypoxic vasodilatation has never been assessed, the factors that mediate this dilatation are poorly defined, and the extent to which the cutaneous circulation is involved in these responses has been largely ignored.Sympathetic activation during hypoxia occurs without measurable increases in plasma noradrenaline, suggesting that hypoxia alters noradrenaline kinetics (release or reuptake). In fact, Leuenberger et al. (1991) found that hypoxia increases noradrenaline re-uptake in humans. Despite these changes in noradrenaline kinetics, it has been shown that in humans, sympathetic vasoconstrictor responses are intact, although blunted. Since hypoxic vasodilatation is observed in human limbs despite a significant rise in sympathetic vasoconstrictor nerve activity, an interesting issue that has yet to be addressed is to what degree these increases in sympathetic nerve activity mask hypoxic vasodilatation.In humans, the whole-limb vasodilatation seen during severe hypoxia can be reduced by b-adrenergic blockade (Richardson et al. 1967; Blauw et al. 1995), suggesting that it is mediated by a b-adrenergic pathway. However, the vasodilatation can also be reduced by nitric oxide (NO) synthase inhibitors (Blitzer et al. 1996), suggesting 1. Limb vascular beds exhibit a graded dilatation in response to hypoxia despite increased sympathetic vasoconstrictor nerve activity. We investigated the extent to which sympathetic vasoconstriction can mask hypoxic vasodilatation and assessed the relative contributions of b-adrenergic and nitric oxide (NO) pathways to hypoxic vasodilatation.2. We measured forearm blood flow responses (plethysmography) to isocapnic hypoxia (arterial saturation ~85 %) in eight healthy men and women (18-26 years) after selective a-adrenergic blockade (phentolamine) of one forearm. Subsequently, we measured hypoxic responses after combined a-and b-adrenergic blockade (phentolamine and propranolol) and after combined aand b-adrenergic blockade coupled with NO synthase inhibition3. Hypoxia increased forearm vascular conductance by 49.0 ± 13.5 % after phentolamine (compared to +16.8 ± 7.0 % in the control arm without phentolamine, P < 0.05). After addition of propranolol, the forearm vascular conductance response to hypoxia was reduced bỹ 50 %, but dilatation was still present (+24.7 ± 7.0 %, P < 0.05 vs. normoxia). When L-NMMA was added, there was no further reduction in the forearm vascular conductance response to hypoxia (+28.2 ± 4.0 %, P < 0.05 vs. normoxia).4. Thus, selective regional a-adrenergic blockade unmasked a greater hypoxic vasodilatation tha...

The purpose of this study was to establish valid indexes of conduit and resistance vessel structure in humans by using edge detection and wall tracking of high-resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, to calculate conduit artery blood flow and diameter continuously across the cardiac cycle. Nine subjects aged 36.7 (9.2) yr underwent, on separate days, assessment of brachial artery blood flow and diameter response to 5-, 10-, and 15-min periods of forearm ischemia in the presence and absence of combined sublingual glyceryl trinitrate (GTN) administration. Two further sessions examined responses to ischemic exercise, one in combination with GTN. The peak brachial artery diameter was observed in response to the combination of ischemic exercise and GTN; a significant difference existed between resting brachial artery diameter and peak brachial artery diameter, indicating that resting diameter may be a poor measure of conduit vessel structure in vivo. Peak brachial artery flow was also observed in response to a combination of forearm ischemia exercise and GTN administration, the response being greater than that induced by periods of ischemia, GTN, or ischemic exercise alone. These data indicate that noninvasive indexes of conduit and resistance vessel structure can be simultaneously determined in vivo in response to a single, brief, stimulus and that caution should be applied in using resting arterial diameter as a surrogate measure of conduit artery structure in vivo.

Pyke K, Green DJ, Weisbrod C, Best M, Dembo L, O'Driscoll G, Tschakovsky ME. Nitric oxide is not obligatory for radial artery flowmediated dilation following release of 5 or 10 min distal occlusion. Am J Physiol Heart Circ Physiol 298: H119 -H126, 2010. First published October 30, 2009 doi:10.1152/ajpheart.00571.2009.-This study investigated the nitric oxide (NO) dependence of radial artery (RA) flowmediated dilation (FMD) in response to three different reactive hyperemia (RH) shear stimulus profiles. Ten healthy males underwent the following three RH trials: 1) 5 min occlusion (5 trial), 2) 10 min occlusion (10 trial), and 3) 10 min occlusion with cuff reinflation at 30 s (10 -30 trial). Trials were performed during saline infusion and repeated during N G -monomethyl-L-arginine (L-NMMA) infusion in the brachial artery. RA blood flow velocity was measured with Doppler ultrasound, and B-mode RA images were analyzed using automated edge detection software. Shear rate estimation of shear stress was calculated as the blood flow velocity/vessel diameter. L-NMMA decreased baseline vascular conductance by 35%. L-NMMA infusion did not affect the peak shear rate stimulus (P ϭ 0.681) or the area under the curve (AUC) of shear rate to peak FMD (P ϭ 0.088). The AUC was significantly larger in the 10 trial vs. the 10 -30 or 5 trial (P Ͻ 0.001). Although percent FMD (%change in diameter) in the 10 trial was larger than that in the 5 trial (P ϭ 0.035), there was no significant difference in %FMD between the saline and L-NMMA conditions in any trial: 5 trial, 5.62 Ϯ 1.48 vs. 5.63 Ϯ 1.27%; 10 trial, 9.07 Ϯ 1.16 vs. 11.22 Ϯ 2.21%; 10 -30 trial, 6.52 Ϯ 1.43 vs. 7.98 Ϯ 1.51% for saline and L-NMMA, respectively (P ϭ 0.158). We conclude the following: 1) RH following 10 min of occlusion results in an enhanced stimulus and %FMD compared with 5 min of occlusion. 2) When the occlusion cuff is reinflated 30 s postrelease of a 10 min occlusion, it does not result in an enhanced %FMD compared with that which results from RH following 5 min of occlusion.3) The lack of effect of L-NMMA on FMD suggests that NO may not be obligatory for radial artery FMD in response to either 5 or 10 min of occlusion in healthy volunteers. nitric oxide; endothelium; shear stress IN HEALTHY ARTERIES, an increase in blood flow (and shear stress) results in endothelial-dependent flow-mediated dilation (FMD) (29,32,41). FMD can therefore serve as an index of endothelial function and provide insight regarding vascular health (42). Originally published by Celermajer et al. (8), the test most commonly performed in humans increases shear stress in conduit arteries (e.g., the brachial, radial, femoral, or popliteal) via reactive hyperemia following the release of temporary limb ischemia (8). A "standard" technique has emerged that stipulates a 5-min cuff occlusion duration, a cuff position distal to the site of conduit artery diameter measurement, and the absence of exercise performed during occlusion (31). The primary reason for these constraints is the desire to cre...

Relative to matched control subjects, Type 2 diabetic subjects exhibit blunted V(E) responses to acute isocapnic hypoxia, suggesting that this group of diabetic subjects possesses a chemoreflex ill-equipped to respond homeostatically to hypoxic challenge.

Relationship between changes in brachial artery flow-mediated dilation and basal release of nitric oxide in subjects with Type 2 diabetes. Am J Physiol Heart Circ Physiol 291: H1193-H1199, 2006. First published March 24, 2006 doi:10.1152/ajpheart.01176.2005.-Assessment of flow-mediated dilation (FMD) after forearm ischemia is widely used as a noninvasive bioassay of stimulated nitric oxide (NO)-mediated conduit artery vasodilator function in vivo. Whether this stimulated endothelial NO function reflects basal endothelial NO function is unknown. To test this hypothesis, retrospective analysis of randomized crossover studies was undertaken in 17 subjects with Type 2 diabetes; 9 subjects undertook an exercise training or control period, whereas the remaining 8 subjects were administered an angiotensin II receptor blocker or placebo. FMD was assessed by using wall tracking of high-resolution brachial artery ultrasound images in response to reactive hyperemia. Resistance vessel basal endotheliumdependent NO function was assessed by using intrabrachial administration of N G -monomethyl-L-arginine (L-NMMA) and plethysmographic assessment of forearm blood flow (FBF). FMD was higher after intervention compared with control/placebo (6.15 Ϯ 0.53 vs. 3.81 Ϯ 0.72%, P Ͻ 0.001). There were no significant changes in the FBF responses to L-NMMA. Regression analysis between FMD and L-NMMA responses at entry to the study revealed an insignificant correlation (r ϭ Ϫ0.10, P ϭ 0.7), and improvements in FMD with the interventions were not associated with changes in the L-NMMA responses (r ϭ Ϫ0.04, P ϭ 0.9). We conclude that conduit arterystimulated endothelial NO function (FMD) does not reflect basal resistance vessel endothelial NO function in subjects with Type 2 diabetes.exercise; acetylcholine; resistance vessel; conduit artery NITRIC OXIDE (NO) bioavailability is thought to play an important atheroprotective role because it inhibits numerous processes implicated in the progression of atherosclerosis, including LDL oxidation, platelet aggregation, monocyte adhesion, and smooth muscle cell proliferation (4,13,30,35). The vascular endothelium releases NO basally (33) and in combination with other vasodilators (e.g., prostacyclin and endothelium-derived hyperpolarizing factor) in response to increases in flow-associated shear stress (25).Anderson et al. (1) were the first to demonstrate that the latter response in a conduit artery results in dilation that could be observed noninvasively via ultrasound imaging (flow-mediated dilation; FMD), whereas Sinoway et al. (32) also provided early evidence for flow-mediated conduit artery dilation. The FMD approach involves a short period of occlusion of the forearm that evokes forearm resistance vessel dilation (11). On release of occlusion, there is a substantial but transient elevation in brachial artery flow velocity providing an increased shear stress stimulus and resulting in FMD.In the early 1990s, Celermajer et al. (5-8) hypothesized and demonstrated that endothelial vasodilator dysfun...