Blood pressure predicts endothelial function and the effects of ethinyl estradiol exposure in young women

Hypertension, obesity, and endothelial function predict cardiovascular disease in women, and these factors are interrelated. We hypothesized that hypertension and obesity are associated with endothelial dysfunction in young women and that short-term ethinyl estradiol exposure mitigates this dysfunction. We examined flow-mediated dilation (FMD) responses before and during 7 days of oral ethinyl estradiol (30 µg/day) in 19 women (25 ± 5, 18–35 yr). We divided our sample into two groups based on two criteria: blood pressure and obesity. Women were divided into normal blood pressure (NBP; mean arterial pressure range: 78–91 mmHg, n = 7) and high blood pressure (HBP; mean arterial pressure range: 95–113 mmHg, n = 9) groups. We also stratified our subjects by body composition (lean: 18–31%, n = 8; obese: 38–59%, n = 9). We evaluated brachial FMD after two distinct shear stress stimuli: occlusion alone and occlusion with ischemic handgrip exercise. Obesity was unrelated to both FMD responses. Before ethinyl estradiol administration, the HBP group had blunted ischemic exercise responses relative to the NBP group (8.0 ± 3.5 vs. 12.3 ± 3.2%, respectively, P = 0.05). However, during ethinyl estradiol administration, ischemic exercise responses increased in the HBP group (12.8 ± 6.1%, P = 0.04) but decreased in the NBP group (5.6 ± 2.4%, P = 0.01). Standard FMD did not reveal differences between groups. In summary, 1) moderate HBP predicted endothelial impairment, 2) ethinyl estradiol administration had divergent effects on FMD in women with NBP versus HBP, and 3) enhanced FMD (ischemic handgrip exercise) revealed differences in endothelial function, whereas standard FMD (occlusion alone) did not. NEW & NOTEWORTHY We are the first to show that mild hypertension is a stronger predictor of endothelial dysfunction than obesity in healthy women without overt cardiovascular dysfunction. Importantly, the standard 5-min flow-mediated vasodilation stimulus did not detect endothelial dysfunction in our healthy population; only an enhanced ischemic handgrip exercise shear stress stimulus detected endothelial impairment. Estradiol administration increased flow-mediated dilation in women with high blood pressure, so it may be a therapeutic intervention to improve endothelial function.

Exercise and arterial adaptation in humans: uncoupling localized and systemic effects

Previous studies have established effects of exercise training on arterial wall thickness, remodeling, and function in humans, but the extent to which these changes are locally or systemically mediated is unclear. We examined the brachial arteries of the dominant (D) and nondominant (ND) upper limbs of elite racquet sportsmen and compared them to those of matched healthy inactive controls. Carotid and superficial femoral artery responses were also assessed in both groups. High-resolution duplex ultrasound was used to examine resting diameter, wall thickness, peak diameter, and blood flow. We found larger resting arterial diameter in the preferred arm of the athletes (4.9 ± 0.5 mm) relative to their nonpreferred arm (4.3 ± 0.4 mm, P < 0.05) and both arms of control subjects (D: 4.1 ± 0.4 mm; ND: 4.0 ± 0.4, P < 0.05). Similar limb-specific differences were also evident in brachial artery dilator capacity (5.5 ± 0.5 vs. 4.8 ± 0.4, 4.8 ± 0.6, and 4.8 ± 0.6 mm, respectively; P < 0.05) following glyceryl trinitrate administration and peak blood flow (1,118 ± 326 vs. 732 ± 320, 737 ± 219, and 698 ± 174 ml/min, respectively; P < 0.05) following ischemic handgrip exercise. In contrast, athletes demonstrated consistently lower wall thickness in carotid (509 ± 55 μm), brachial (D: 239 ± 100 μm; ND: 234 ± 133 μm), and femoral (D: 479 ± 38 μm; ND: 479 ± 42 μm) arteries compared with control subjects (carotid: 618 ± 74 μm; brachial D: 516 ± 100 μm; ND: 539 ± 129 μm; femoral D: 634 ± 155 μm; ND: 589 ± 112 μm; all P < 0.05 vs. athletes), with no differences between the limbs of either group. These data suggest that localized effects of exercise are evident in the remodeling of arterial size, whereas arterial wall thickness appears to be affected by systemic factors.

Repeated increases in blood flow, independent of exercise, enhance conduit artery vasodilator function in humans

This study aimed to determine the importance of repeated increases in blood flow to conduit artery adaptation, using an exercise-independent repeated episodic stimulus. Recent studies suggest that exercise training improves vasodilator function of conduit arteries via shear stress-mediated mechanisms. However, exercise is a complex stimulus that may induce shear-independent adaptations. Nine healthy men immersed their forearms in water at 42°C for three 30-min sessions/wk across 8 wk. During each session, a pneumatic pressure cuff was inflated around one forearm to unilaterally modulate heating-induced increases in shear. Forearm heating was associated with an increase in brachial artery blood flow ( P < 0.001) and shear rate ( P < 0.001) in the uncuffed forearm; this response was attenuated in the cuffed limb ( P < 0.005). Repeated episodic exposure to bilateral heating induced an increase in endothelium-dependent vasodilation in response to 5-min ischemic ( P < 0.05) and ischemic handgrip exercise ( P < 0.005) stimuli in the uncuffed forearm, whereas the 8-wk heating intervention did not influence dilation to either stimulus in the cuffed limb. Endothelium-independent glyceryl trinitrate responses were not altered in either limb. Repeated heating increases blood flow to levels that enhance endothelium-mediated vasodilator function in humans. These findings reinforce the importance of the direct impacts of shear stress on the vascular endothelium in humans.

WISE 2005: stroke volume changes contribute to the pressor response during ischemic handgrip exercise in women

The mechanism of the pressor response to small muscle mass (e.g., forearm) exercise and during metaboreflex activation may include elevations in cardiac output (Q̇) or total peripheral resistance (TPR). Increases in Q̇ must be supported by reductions in visceral venous volume to sustain venous return as heart rate (HR) increases. Therefore, this study tested the hypothesis that increases in Q̇, supported by reductions in splanchnic volume (portal vein constriction), explain the pressor response during handgrip exercise and metaboreflex activation. Seventeen healthy women performed 2 min of static ischemic handgrip exercise and 2 min of postexercise circulatory occlusion (PECO) while HR, stroke volume and superficial femoral artery flow (Doppler), blood pressure (Finometer), portal vein diameter (ultrasound imaging), and muscle sympathetic nerve activity (MSNA; microneurography) were measured followed by the calculation of Q̇, TPR, and leg vascular resistance (LVR). Compared with baseline, mean arterial blood pressure (MAP) ( P < 0.001) and Q̇ ( P < 0.001) both increased in each minute of exercise accompanied by a ∼5% reduction in portal vein diameter ( P < 0.05). MAP remained elevated during PECO, whereas Q̇ decreased below exercise levels. MSNA was elevated above baseline during the second minute of exercise and through the PECO period ( P < 0.05). Neither TPR nor LVR was changed from baseline during exercise and PECO. The data indicate that the majority of the blood pressure response to isometric handgrip exercise in women was due to mobilization of central blood volume and elevated stroke volume and Q̇ rather than elevations in TVR or LVR resistance.

Measurement of limb venous compliance in humans: technical considerations and physiological findings

We conducted a series of studies to develop and test a rapid, noninvasive method to measure limb venous compliance in humans. First, we measured forearm volume (mercury-in-Silastic strain gauges) and antecubital intravenous pressure during inflation of a venous collecting cuff around the upper arm. Intravenous pressure fit the regression line, −0.3 ± 0.7 + 0.95 ± 0.02 ⋅ cuff pressure ( r = 0.99 ± 0.00), indicating cuff pressure is a good index of intravenous pressure. In subsequent studies, we measured forearm and calf venous compliance by inflating the venous collecting cuff to 60 mmHg for 4 min, then decreasing cuff pressure at 1 mmHg/s (over 1 min) to 0 mmHg, using cuff pressure as an estimate of venous pressure. This method produced pressure-volume curves fitting the quadratic regression (Δlimb volume) = β0 + β1 ⋅ (cuff pressure) + β2 ⋅ (cuff pressure)2, where Δ is change. Curves generated with this method were reproducible from day to day (coefficient of variation: 4.9%). In 11 subjects we measured venous compliance via this method under two conditions: with and without (in random order) superimposed sympathetic activation (ischemic handgrip exercise to fatigue followed by postexercise ischemia). Calf and forearm compliance did not differ between control and sympathetic activation ( P > 0.05); however, the data suggest that unstressed volume was reduced by the maneuver. These studies demonstrate that venous pressure-volume curves can be generated both rapidly and noninvasively with this technique. Furthermore, the results suggest that although whole-limb venous compliance is under negligible sympathetic control in humans, unstressed volume can be affected by the sympathetic nervous system.