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In 2017, the American Heart Association (AHA) and American College of Cardiology (ACC) redefined stage 1 hypertension to systolic blood pressure (BP) 130-139 mmHg or diastolic BP 80-89 mmHg; however, the degree to which microvascular endothelial dysfunction is evident in adults with stage 1 hypertension remains equivocal. We tested the hypotheses that cutaneous microvascular endothelial dysfunction would be present in adults with stage 1 hypertension (HTN1) compared with normotensive adults (NTN; BP <120/<80 mmHg) but would be less severe compared with adults with stage 2 hypertension (HTN2; systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and that this graded impairment would be mediated by reductions in nitric oxide (NO)-dependent dilation. This retrospective analysis included 20 NTN (5 men; 45-64 yr; BP 94-114/60-70 mmHg), 22 HTN1 (11 men; 40-74 yr; BP 110-134/70-88 mmHg), and 44 HTN2 (27 men; 40-74 yr; BP 128-180/80-110 mmHg). BP and nocturnal dipping status were also assessed using 24-h ambulatory BP monitoring. Red cell flux (laser Doppler flowmetry) was measured during intradermal microdialysis perfusion of acetylcholine (ACh; 10 -10 to 10 -1 M) alone and concurrently with the nonspecific nitric oxide (NO) synthase inhibitor N G -nitro-l-arginine methyl ester (l-NAME; 15 mM). ACh-induced dilation was impaired in HTN2 ( P < 0.01), but not in HTN1 ( P = 0.85), compared with NTN. Furthermore, reductions in NO-dependent dilation were evident in HTN2 ( P < 0.01) but not in HTN1 ( P = 0.76). Regardless of BP, endothelium-dependent dilation was impaired in nondippers (nighttime drop in systolic BP <10%) compared with dippers (nighttime drop in systolic BP ≥10%, P < 0.05). In conclusion, functional impairments in NO-mediated endothelium-dependent dilation were not evident in HTN1. However, regardless of BP classification, the lack of a nocturnal dip in BP was associated with blunted endothelium-dependent dilation. NEW & NOTEWORTHY This is the first study to pharmacologically assess the mechanistic regulation of endothelial function in adults with hypertension, classified according to the 2017 clinical guidelines set for by the American Heart Association (AHA) and American College of Cardiology (ACC). Compared with that in normotensive adults, nitric oxide-mediated endothelium-dependent dilation is impaired in adults with stage 2, but not stage 1, hypertension. Adults lacking a nighttime dip in blood pressure demonstrated reductions in endothelium-dependent dilation.

Patients with coronary artery disease have attenuated coronary vasodilator responses to physiological stress, which is partially attributed to a β-adrenergic receptor (β-AR)-mediated mechanisms. Whether β-ARs contribute to impaired coronary vasodilation seen with healthy aging is unknown. The purpose of this study was to investigate the role of β-ARs in coronary exercise hyperemia in healthy humans. Six young men (26 ± 1 yr) and seven older men (67 ± 4 yr) performed isometric handgrip exercise at 30% maximal voluntary contraction for 2 min after receiving intravenous propranolol, a β-AR antagonist, and no treatment. Isoproterenol, a β-AR agonist, was infused to confirm the β-AR blockade. Blood pressure and heart rate were monitored continuously, and coronary blood flow velocity (CBV, left anterior descending artery) was measured by transthoracic Doppler echocardiography. Older men had an attenuated ΔCBV to isometric exercise (3.8 ± 1.3 vs. 9.7 ± 2.1 cm/s, P = 0.02) compared with young men. Propranolol decreased the ΔCBV at peak handgrip exercise in young men (9.7 ± 2.1 vs. 2.7 ± 0.9 cm/s, P = 0.008). However, propranolol had no effect on ΔCBV in older men (3.8 ± 1.3 vs. 4.2 ± 1.9 cm/s, P = 0.9). Older men also had attenuated coronary hyperemia to low-dose isoproterenol. These data indicate that β-AR control of coronary blood flow is impaired in healthy older men., (Copyright © 2014 the American Physiological Society.)

Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole + L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial Po2 ~37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole + L-NMMA reduced (P < 0.05) forearm vascular conductance (FVC) by ~10% and ~18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 ± 0.37 and 0.95 ± 0.35 units in control and experimental forearms, respectively (P < 0.05). During hypoxia and fluconazole + L-NMMA (trial 2), FVC increased by 2.32 ± 0.51 and 0.72 ± 0.22 units in control and experimental forearms, respectively (P < 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n = 8) FVC increased by 1.51 ± 0.46 and 0.45 ± 0.32 units in control and experimental forearms, respectively (P < 0.05). These effects were not due to altered skin blood flow. We conclude that endothelium-derived hyperpolarizing factor contributes to basal vascular tone and to hypoxia-induced skeletal muscle vasodilation and could be particularly relevant when other vasodilator systems are impaired.

We recently showed that a fixed volume (i.e., 40 ml) of saline infused into the venous circulation of an arterially occluded vascular bed increases muscle sympathetic nerve activity (MSNA) and blood pressure. In the present report, we hypothesized that the volume and rate of infusion would influence the magnitude of the sympathetic response. Blood pressure, heart rate, and MSNA were assessed in 13 young healthy subjects during forearm saline infusions (arrested circulation). The effects of different volumes of saline (i.e., 2%, 3%, 4%, or 5% forearm volume at 30 ml/min) and different rates of infusion (i.e., 5% forearm volume at 10, 20, or 30 ml/min) were evaluated. MSNA and blood pressure responses were linked with the infusion volume. Infusion of 5% of forearm volume evoked greater MSNA responses than did infusion of 2% of forearm volume (Δ11.6 ± 1.9 vs. Δ3.1 ± 1.8 bursts/min and Δ332 ± 105 vs. Δ38 ± 32 units/min, all P < 0.05). Moreover, greater MSNA responses were evoked by saline infusion at 30 ml/min than 10 ml/min (P < 0.05). Sonographic measurements confirmed that the saline infusions induced forearm venous distension. The results suggest that volume and rate of saline infusion are important factors in evoking sympathetic activation. We postulate that venous distension contributes to cardiovascular autonomic adjustment in humans.

Obstructive sleep apnea (OSA) is associated with increased sympathetic nerve activity, endothelial dysfunction, and premature cardiovascular disease. To determine whether hypoxia is associated with impaired skeletal muscle vasodilation, we compared femoral artery blood flow (ultrasound) and muscle sympathetic nerve activity (peroneal microneurography) during exposure to acute systemic hypoxia (fraction of inspired oxygen 0.1) in awake patients with OSA (n=10) and controls (n=8). To assess the role of elevated sympathetic nerve activity, in a separate group of patients with OSA (n=10) and controls (n=10) we measured brachial artery blood flow during hypoxia before and after regional alpha-adrenergic block with phentolamine. Despite elevated sympathetic activity, in OSA the vascular responses to hypoxia in the leg did not differ significantly from those in controls [P=not significant (NS)]. Following regional phentolamine, in both groups the hypoxia-induced increase in brachial blood flow was markedly enhanced (OSA pre vs. post, 84+/-13 vs. 201+/-34 ml/min, P<0.002; controls pre vs. post 62+/-8 vs. 140+/-26 ml/min, P<0.01). At end hypoxia after phentolamine, the increase of brachial blood flow above baseline was similar (OSA vs. controls +61+/-16 vs. +48+/-6%; P=NS). We conclude that despite high sympathetic vasoconstrictor tone and prominent sympathetic responses to acute hypoxia, hypoxia-induced limb vasodilation is preserved in OSA.

Human studies of coronary circulation are limited because of methodological issues. Recently, a noninvasive transthoracic duplex ultrasound (TTD) technique has emerged as an important tool to measure coronary blood flow velocity (CBV) in conscious humans. We employed two protocols to determine whether noninvasive "native" coronary artery velocity responses to constrictor or dilator stimuli assessed by TTD provide reliable data. In the first protocol, coronary vascular resistance (CVR = diastolic blood pressure/CBV) responses to static handgrip were examined in the left internal mammary artery (LIMA) and native left anterior descending artery (LAD) into which the graft was inserted (patient age 63 +/- 3 years). Our prior report documented increased CVR in the LIMA graft during static handgrip (Momen et al., J Appl Physiol 102: 735-739, 2007). We hypothesized that the magnitude of increases in CVR during handgrip would be similar in the LIMA graft and LAD in the same individual. Percent increases in CVR were similar in the LIMA and distal native LAD (27 +/- 4% vs. 28 +/- 6%). In the second protocol, we studied six patients (age 61 +/- 3 years) who underwent cardiac catheterization of the LAD. We compared coronary vasodilator responses to intravenous adenosine infusion (0.14 mg.kg(-1).min(-1)) obtained by intracoronary Doppler guidewire technique and TTD on separate studies. The relative increases in CBV with adenosine obtained by intracoronary Doppler guidewire and TTD were similar (62 +/- 10% vs. 65 +/- 12%). Noninvasive TTD provides reliable human coronary circulatory constrictor and dilator data.

Animal reports suggest that reflex activation of cardiac sympathetic nerves can evoke coronary vasoconstriction. Conversely, physiological stress may induce coronary vasodilation to meet an increased metabolic demand. Whether the sympathetic nervous system can modulate coronary vasomotor tone in response to stress in humans is unclear. Coronary blood velocity (CBV), an index of coronary blood flow, can be measured in humans by noninvasive duplex ultrasound. We studied 11 healthy volunteers and measured beat-by-beat changes in CBV, blood pressure, and heart rate during 1) static handgrip for 20 s at 10% and 70% of maximal voluntary contraction; 2) lower body negative pressure at -10 and -30 mmHg for 3 min each; 3) cold pressor test for 90 s; and 4) hypoxia (10% O(2)), hyperoxia (100% O(2)), and hypercapnia (5% CO(2)) for 5 min each. At the higher level of handgrip, mean blood pressure increased (P < 0.001), whereas CBV did not change [P = not significant (NS)]. In addition, during lower body negative pressure, CBV decreased (P < 0.02; and P < 0.01, for -10 and -30 mmHg, respectively), whereas blood pressure did not change (P = NS). The dissociation between the responses of CBV and blood pressure to handgrip and lower body negative pressure is consistent with coronary vasoconstriction. During hypoxia, CBV increased (P < 0.02) and decreased during hyperoxia (P < 0.01), although blood pressure did not change (P = NS), suggesting coronary vasodilation during hypoxia and vasoconstriction during hyperoxia. In contrast, concordant increases in CBV and blood pressure were noted during the cold pressor test, and hypercapnia had no effects on either parameter. Thus the physiological stress known to be associated with sympathetic activation can produce coronary vasoconstriction in humans. Contrasting responses were noted during systemic hypoxia and hyperoxia where mechanisms independent of autonomic influences appear to dominate the vascular end-organ effects.

The extent to which sympathetic nerve activity restrains metabolic vasodilation in skeletal muscle remains unclear. We determined forearm blood flow (FBF; ultrasound/Doppler) and vascular conductance (FVC) responses to 10 min of ischemia [reactive hyperemic blood flow (RHBF)] and 10 min of systemic hypoxia (inspired O(2) fraction = 0.1) before and after regional sympathetic blockade with the alpha-receptor antagonist phentolamine via Bier block in healthy humans. In a control group, we performed sham Bier block with saline. Consistent with alpha- receptor inhibition, post-phentolamine, basal FVC (FBF/mean arterial pressure) increased (pre vs. post: 0.42 +/- 0.05 vs. 1.03 +/- 0.21 units; P < 0.01; n = 12) but did not change in the saline controls (pre vs. post: 0.56 +/- 0.14 vs. 0.53 +/- 0.08 units; P = not significant; n = 5). Post-phentolamine, total RHBF (over 3 min) increased substantially (pre vs. post: 628 +/- 75 vs. 826 +/- 92 ml/min; P < 0.01) but did not change in the controls (pre vs. post: 618 +/- 66 vs. 661 +/- 35 ml/min; P = not significant). In all conditions, compared with peak RHBF, peak skin reactive hyperemia was markedly delayed. Furthermore, post-phentolamine (pre vs. post: 0.43 +/- 0.06 vs. 1.16 +/- 0.17 units; P < 0.01; n = 8) but not post-saline (pre vs. post: 0.93 +/- 0.16 vs. 0.87 +/- 0.19 ml/min; P = not significant; n = 5), the FVC response to hypoxia (arterial O(2) saturation = 77 +/- 1%) was markedly enhanced. These data suggest that sympathetic vasoconstrictor nerve activity markedly restrains skeletal muscle vasodilation induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli.

Forearm endothelium-dependent vasodilation is impaired with age in sedentary, but not endurance-trained, men. The purpose of this investigation was to determine whether these age- and physical activity-related differences in endothelium-dependent vasodilation also occur in the leg. Brachial and common femoral arterial blood flow were measured with Doppler ultrasound during increasing doses of acetylcholine (1, 4, and 16 microg.100 ml limb tissue(-1).min(-1)), substance P (8, 31, and 125 pg.100 ml limb tissue(-1).min(-1)), and sodium nitroprusside (0.063, 0.25, and 1 microg.100 ml limb tissue(-1).min(-1)) in 23 healthy men (8 younger sedentary, 8 older sedentary, and 7 older endurance trained). Increases in forearm blood flow to the highest dose of acetylcholine and sodium nitroprusside were smaller (P < 0.05) in older sedentary (841 +/- 142%, 428 +/- 74%) compared with younger sedentary (1,519 +/- 256%, 925 +/- 163%) subjects. Similarly, increases in forearm blood flow to sodium nitroprusside (1 microg.100 ml limb tissue(-1).min(-1)) were smaller (P < 0.05) in older endurance-trained (505 +/- 110%) compared with younger sedentary (925 +/- 163%) subjects. In contrast, no differences in leg blood flow responses to intra-arterial infusions of acetylcholine, substance P, or sodium nitroprusside were noted between subject groups. These results demonstrate that 1) acetylcholine- and sodium nitroprusside-induced vasodilation are attenuated in the forearm vasculature and preserved in the leg vasculature of older sedentary subjects and 2) sodium nitroprusside-induced vasodilation remains attenuated in the forearm vasculature of healthy older endurance-trained men but preserved in the leg vasculature of these men.

Forearm vascular responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators have been thoroughly characterized in humans. While the forearm is a well-established experimental model for studying human vascular function, it is of limited consequence to systemic cardiovascular control owing to its small muscle mass and blood flow requirements. In the present study we determined whether these responses could be generalized to the leg. Based upon blood pressure differences between the leg and arm during upright posture, we hypothesized that the responsiveness to endothelium-dependent vasodilators would be greater in the forearm than the leg. Brachial and femoral artery blood flow (Q, ultrasound Doppler) at rest and during intra-arterial infusions of endothelium-dependent (acetylcholine and substance P) and -independent (sodium nitroprusside) vasodilators were measured in eight healthy men (22-27 years old). Resting blood flows in the forearm before infusion of acetylcholine, substance P or sodium nitroprusside were 25 +/- 4, 30 +/- 7 and 29 +/- 5 ml min(-1), respectively, and in the leg were 370 +/- 32, 409 +/- 62 and 330 +/- 30 ml min(-1), respectively. At the highest infusion rate of acetylcholine (16 microg (100 ml tissue)(-1) min(-1)) there was a greater (P < 0.05) increase in Q to the forearm (1864 +/- 476%) than to the leg (569 +/- 86%). Similarly, at the highest infusion rate of substance P (125 pg (100 ml tissue)(-1) min(-1)) there was a greater (P < 0.05) increase in Q to the forearm (911 +/- 286%) than to the leg (243 +/- 58%). The responses to sodium nitroprusside (1 microg (100 ml tissue)(-1) min(-1)) were also greater (P < 0.05) in the forearm (925 +/- 164%) than in the leg (326 +/- 65%). These data indicate that vascular responses to both endothelium-dependent and -independent vasodilator agents are blunted in the leg compared to the forearm.

The purpose of the present study was to test the hypothesis that leg blood flow responses during leg cycle ergometry are reduced with age in healthy non-estrogen-replaced women. Thirteen younger (20-27 yr) and thirteen older (61-71 yr) normotensive, non-endurance-trained women performed both graded and constant-load bouts of leg cycling at the same absolute exercise intensities. Leg blood flow (femoral vein thermodilution), mean arterial pressure (MAP; radial artery), mean femoral venous pressure, cardiac output (acetylene rebreathing), and blood O2 contents were measured. Leg blood flow responses at light workloads (20-40 W) were similar in younger and older women. However, at moderate workloads (50-60 W), leg blood flow responses were significantly attenuated in older women. MAP was 20-25 mmHg higher (P < 0.01) in the older women across all work intensities, and calculated leg vascular conductance (leg blood flow/estimated leg perfusion pressure) was lower (P < 0.05). Exercise-induced increases in leg arteriovenous O2 difference and O2 extraction were identical between groups (P > 0.6). Leg O2 uptake was tightly correlated with leg blood flow across all workloads in both subject groups (r2 = 0.80). These results suggest the ability of healthy older women to undergo limb vasodilation in response to submaximal exercise is impaired and that the legs are a potentially important contributor to the augmented systemic vascular resistance seen during dynamic exercise in older women.

Obstructive sleep apnea causes cardiovascular morbidity and premature death. Potential links between sleep apnea and cardiovascular complications are chronically elevated activity of the sympathetic nervous system and abnormal vascular function. To explore vascular function, we determined the reactive hyperemic blood flow (RHBF) responses to 10 minutes of forearm arterial occlusion (plethysmography), blood pressure, and muscle sympathetic nerve activity (MSNA, microneurography) in eight patients with sleep apnea and in nine nonapneic control subjects. Peak RHBF and vascular conductance were markedly attenuated in sleep apnea compared with control subjects (p < 0.05). Seven sleep apnea patients were retested after at least two weeks of continuous positive airway pressure (CPAP) therapy. MSNA decreased after CPAP therapy (p < 0.05, n = 6), whereas blood pressure did not change. After CPAP therapy, peak RHBF and vascular conductance were increased compared with before treatment (p < 0.05; n = 7). Thus, vascular function is abnormal in sleep apnea and is improved by CPAP therapy. Furthermore, effective CPAP therapy decreases sympathetic activity in sleep apnea. Thus, sympathoexcitation and abnormal vascular function in patients with sleep apnea appear to be linked to the repetitive nocturnal apneic events.

In humans, hypoxia leads to increased sympathetic neural outflow to skeletal muscle. However, blood flow increases in the forearm. The mechanism of hypoxia-induced vasodilation is unknown. To test whether hypoxia-induced vasodilation is cholinergically mediated or is due to local release of adenosine, normal subjects were studied before and during acute hypoxia (inspired O(2) 10.5%; approximately 20 min). In experiment I, aminophylline (50-200 microg. min(-1). 100 ml forearm tissue(-1)) was infused into the brachial artery to block adenosine receptors (n = 9). In experiment II, cholinergic vasodilation was blocked by atropine (0.4 mg over 4 min) infused into the brachial artery (n = 8). The responses of forearm blood flow (plethysmography) and forearm vascular resistance to hypoxia in the infused and opposite (control) forearms were compared. During hypoxia (arterial O(2) saturation 77 +/- 2%), minute ventilation and heart rate increased while arterial pressure remained unchanged; forearm blood flow rose by 35 +/- 6% in the control forearm but only by 5 +/- 8% in the aminophylline-treated forearm (P < 0.02). Accordingly, forearm vascular resistance decreased by 29 +/- 5% in the control forearm but only by 9 +/- 6% in the aminophylline-treated forearm (P < 0.02). Atropine did not attenuate forearm vasodilation during hypoxia. These data suggest that adenosine contributes to hypoxia-induced vasodilation, whereas cholinergic vasodilation does not play a role.