Women experience orthostatic intolerance more than men, and they experience faintness more in the early follicular [i.e., low-hormone (LH)] than luteal [i.e., high-hormone (HH)] phase of the menstrual cycle. Men ( = 13, 25.8 ± 1.8 yr old) and women in the LH (; placebo) and HH (; high dose) phases of the menstrual cycle with (OC; = 14, 22.0 ± 0.8 yr old) or without (NOC; = 12, 21.8 ± 0.5 yr old) oral contraceptive (OC) use underwent the Valsalva maneuver and a supine-sit-stand protocol. Blood pressure, normalized stroke volume [stroke volume index (SVi)], cardiac output index, heart rate, end-tidal CO, and middle cerebral artery (MCA) blood flow velocity were measured. When subjected to the Valsalva maneuver, all women had a greater increase in diastolic and mean MCA blood flow velocity than men ( ≤ 0.065), with no significant effect of menstrual cycle phase or OC use. When subjected to the supine-sit-stand protocol, men had lower MCA blood flow velocity ( < 0.038) than all women, and SVi was higher in men than in the NOC group in all postures ( < 0.011) and in the OC group in the LH phase of the menstrual cycle during standing ( = 0.010). Only men experienced higher resistance index ( < 0.001) and pulsatility index ( < 0.001) with standing. The OC group had lower end-tidal CO ( = 0.002) than the NOC group ( = 0.030) and men ( ≤ 0.067). SVi ( = 0.004) and cardiac output index ( = 0.008) were higher in the OC than NOC group. A tendency toward a lower mean MCA blood flow velocity ( = 0.058) and higher SVi ( = 0.059) and pulsatility index ( = 0.058) was noted in the HH than LH phase. Mean arterial pressure was higher in the OC than NOC group in the LH phase ( = 0.049) and lower in the HH than LH phase ( = 0.014). Our results indicate that cycling estrogens/progestins can influence ventilatory, cardiovascular, and/or cerebrovascular physiology. We have found sex differences in the cerebrovascular response to the Valsalva maneuver and standing. Men have greater cerebral vasoconstriction (or women have greater cerebral vasodilation) during late phase II of the Valsalva maneuver, and the cerebrovascular resistance index increases in men, but not in women, during standing. Furthermore, our findings indicate that both the menstrual cycle phase and oral contraceptive use can influence cardiovascular function both at rest and during active standing.

Edgell H, Robertson AD, Hughson RL. Hemodynamics and brain blood flow during posture change in younger women and postmenopausal women compared with age-matched men. J Appl Physiol 112: 1482-1493, 2012. First published February 23, 2012 doi:10.1152/japplphysiol.01204.2011.-Increased incidence of orthostatic hypotension and presyncopal symptoms in young women could be related to hormonal factors that might be isolated by comparing cardiovascular and cerebrovascular responses to postural change in young and older men and women. Seven young women, 11 young men, 10 older women (Ͼ1 yr postmenopausal, no hormone therapy), and 9 older men participated in a supine-to-sit-to-stand test while measuring systemic hemodynamics, end-tidal PCO2, and blood flow velocity of the middle cerebral artery (MCA). Women had a greater reduction in stroke volume index compared with age-matched men (change from supine to standing: young women: Ϫ22.9 Ϯ 1.6 ml/m 2 ; young men: Ϫ14.4 Ϯ 2.4 ml/m 2 ; older women: Ϫ17.4 Ϯ 3.3 ml/m 2 ; older men: Ϫ13.8 Ϯ 2.2 ml/m 2 ). This was accompanied by offsetting changes in heart rate, particularly in young women, resulting in no age or sex differences in cardiac output index. Mean arterial pressure (MAP) was higher in older subjects and increased with movement to upright postures. Younger men and women had higher forearm vascular resistance that increased progressively in the upright posture compared with older men and women. There was no difference between sexes or ages in total peripheral resistance index. Women had higher MCA velocity, but both sexes had reduced MCA velocity while upright, which was a function of reduced blood pressure at the MCA and a significant reduction in end-tidal PCO2. The reductions in stroke volume index suggested impaired venous return in women, but augmented responses of heart rate and forearm vascular resistance protected MAP in younger women. Overall, these results showed significant sex and age-related differences, but compensatory mechanisms preserved MAP and MCA velocity in young women. cerebrovascular; sex; age; orthostatic ORTHOSTATIC HYPOTENSION (a condition that sometimes leads to fainting) is an important and sometimes dangerous condition that particularly affects young women during daily life, as reflected by admission to emergency rooms (51). It has been speculated that female sex hormones might modulate reflex neural or vascular properties, resulting in the greater incidence of orthostatic hypotension in young women (5,14,15,52,69). An additional indication of impaired orthostatic responses in women includes the observation that women have a greater propensity towards postural orthostatic tachycardia syndrome (18, 60).Contrary to observations for young women, clinical evidence supports the concept that orthostatic hypotension occurs less frequently in women ages 40 -60 yr (many of whom could be postmenopausal) (51). Investigations of men and women from 23-77 yr of age indicated that the heart rate response to tilt was reduced with aging, but vascular responses a...

COPD is associated with elevated cardiovascular risk and a potentiated ventilatory response to exercise. Enhanced carotid chemoreceptor (CC) activity/sensitivity is present in other clinical conditions, has been shown to contribute to sympathetic vasoconstrictor outflow, and is predictive of mortality. CC activity/sensitivity, and the resulting functional significance, has not been well examined in COPD. We hypothesized that CC activity/sensitivity would be elevated in COPD, and related to increased pulse wave velocity (a marker of CV risk) and the ventilatory response to exercise. Methods: 30 COPD patients and 10 healthy age-matched controls were examined. Participants performed baseline cardiopulmonary exercise and pulmonary function testing. CC activity was later evaluated by the drop in ventilation with breathing 100% O2, and CC sensitivity was then assessed by the ventilatory response to hypoxia (ΔVE/ΔSpO2). Peripheral arterial stiffness was subsequently evaluated by measurement of pulse wave velocity (PWV) using applanation tonometry while the subjects were breathing room air, and then following chemoreceptor inhibition by breathing 100% O2 for 2 minutes. Results: CC activity, CC sensitivity, PWV and the ventilatory response to exercise were all increased in COPD relative to controls. CC sensitivity was related to PWV; however, neither CC activity nor CC sensitivity was related to the ventilatory response to exercise in COPD. CC inhibition by breathing 100% O2 normalized PWV in COPD, while no effect was observed in controls. Conclusion: CC activity and sensitivity are elevated in COPD, and appear related to cardiovascular risk; however, CC activity/sensitivity does not contribute to the potentiated ventilatory response to exercise.

Edgell H, Stickland MK. Activation of the carotid chemoreflex secondary to muscle metaboreflex stimulation in men. Am J Physiol Regul Integr Comp Physiol 306: R693-R700, 2014. First published February 26, 2014 doi:10.1152 doi:10. /ajpregu.00472.2013 has shown that the carotid chemoreceptor (CC) contributes to sympathetic control of cardiovascular function during exercise, despite no evidence of increased circulating CC stimuli, suggesting enhanced CC activity/sensitivity. As interactions between metaboreceptors and chemoreceptors have been previously observed, the purpose of this study was to isolate the metaboreflex while acutely stimulating or inhibiting the CC to determine whether the metaboreflex increased CC activity/sensitivity. Fourteen young healthy men (height: 177.0 Ϯ 2.1 cm, weight: 85.8 Ϯ 5.5 kg, age: 24.6 Ϯ 1.1 yr) performed three trials of 40% maximal voluntary contraction handgrip for 2 min, followed by 3 min of postexercise circulatory occlusion (PECO) to stimulate the metaboreflex. In random order, subjects either breathed room air, hypoxia (target SPO 2 ϭ 85%), or hyperoxia (FIO 2 ϭ 1.0) during the PECO to modulate the chemoreflex. After these trials, a resting hypoxia trial was conducted without handgrip or PECO. Ventilation (V E), heart rate (HR), blood pressure, and muscle sympathetic nervous activity (MSNA) data were continuously obtained. Relative to normoxic PECO, inhibition of the CC during hyperoxic PECO resulted in lower MSNA (P ϭ 0.038) and HR (P ϭ 0.021). Relative to normoxic PECO, stimulation of the CC during hypoxic PECO resulted in higher HR (P Ͻ 0.001) and V E (P Ͻ 0.001). The ventilatory and MSNA responses to hypoxic PECO were not greater than the sum of the responses to hypoxia and PECO individually, indicating that the CC are not sensitized during metaboreflex activation. These results demonstrate that stimulation of the metaboreflex activates, but does not sensitize the CC, and help explain the enhanced CC activity with exercise. sympathetic nerve activity; ventilation; exercise EXERCISE is known to involve cardiovascular influences from metaboreceptors, mechanoreceptors, baroreceptors, and central command (25). The carotid chemoreceptor has been shown to be activated/sensitized during exercise (10,27,33,40). Previous work has provided evidence that the carotid chemoreceptor is enhanced with exercise despite no change in circulating carotid chemoreceptor stimuli (K ϩ , lactate, pH, PCO 2 , PO 2 ), and that carotid chemoreceptor inhibition with either dopamine or hyperoxia increases cardiac output and/or peripheral blood flow during exercise secondary to a reduction in sympathetic vasoconstrictor outflow (32-34). Similarly, rhythmic handgrip exercise in humans activates/sensitizes the carotid chemoreceptor despite no increase in blood lactate (34); however, the exact mechanism behind this activation/sensitization of the carotid chemoreceptor during exercise is unknown.Conflicting evidence exists concerning the role of muscle afferents on exercise-induced carotid chemorecepto...

Peripheral chemoreceptor activity/sensitivity is enhanced in chronic heart failure (HF), and sensitivity is linked to greater mortality. This study aimed to determine the role of the peripheral chemoreceptor in cardiovascular control at rest and during exercise in HF patients and controls. Clinically stable HF patients (n = 11; ejection fraction: 39 ± 5%) and risk-matched controls (n = 10; ejection fraction: 65 ± 2%) performed randomized trials with or without dopamine infusion (2 μg·min(-1)·kg(-1)) at rest and during 40% maximal voluntary contraction handgrip (HG) exercise, and a resting trial of 2 min of inspired 100% oxygen. Both dopamine and hyperoxia were used to inhibit the peripheral chemoreceptor. At rest in HF patients, dopamine decreased ventilation (P = 0.02), decreased total peripheral resistance index (P = 0.003), and increased cardiac and stroke indexes (P ≤ 0.01), yet there was no effect of dopamine on these variables in controls (P ≥ 0.7). Hyperoxia lowered ventilation in HF (P = 0.01), but not in controls (P = 0.9), indicating suppression of the peripheral chemoreceptors in HF. However, no decrease of total peripheral resistance index was observed in HF. As expected, HG increased heart rate, ventilation, and brachial conductance of the nonexercising arm in controls and HF patients. During dopamine infusion, there were no changes in mean arterial pressure, heart rate, or ventilation responses to HG in either group (P ≥ 0.26); however, brachial conductance increased with dopamine in the control group (P = 0.004), but decreased in HF (P = 0.02). Our findings indicate that the peripheral chemoreceptor contributes to cardiovascular control at rest in HF patients and during exercise in risk-matched controls.

We tested the hypotheses that estrogen replacement in ovariectomized (OVX) rats attenuates cardiovascular responses to psychological stress and that nitric oxide (NO) in the brain mediates these effects. Female rats were OVX; one group received 17beta-estradiol (OVX-E) for 11-12 days and the other received vehicle (OVX-V). Seven days after OVX, OVX-E and OVX-V rats were chronically instrumented for arterial pressure measurements and intracerebroventricular injections. Later (4-5 days), OVX-E and OVX-V rats received intracerebroventricular injections of NG-nitro-l-arginine (88 microg/kg), an inhibitor of constitutive NO production, or vehicle. Mean arterial pressure (MAP) and heart rate responses were then measured in conscious rats exposed to two cycles of 1-h restraint/1-h rest. We show that MAP responses in restrained OVX-E rats were attenuated both during restraint and during rest. Although inhibition of NO production in the brain had no effect on MAP responses to restraint in OVX-V rats, it augmented responses in restrained OVX-E rats, especially during periods of rest, so that MAPs in restrained OVX-E and OVX-V rats were indistinguishable. Finally, NO levels in hypothalami and brain stems were elevated in restrained OVX-E, but not OVX-V, rats compared with their respective unrestrained controls. These results show that estrogen replacement in OVX rats reduces arterial pressure responses to psychological stress and that these effects are mediated, at least in part, by NO.

We tested the hypotheses that women completing 56 days, 6 degrees head-down bed-rest (HDBR) would have changes in sensitivity of cardiovascular responses to adrenergic receptor stimulation and that frequent aerobic and resistive exercise would prevent these changes. Twenty-four women, eight controls, eight exercisers (lower body negative pressure treadmill and flywheel resistance exercise), and eight receiving nutritional supplement but no exercise were studied in baseline and during administration of the beta-agonist isoproterenol (ISO) and the alpha- and beta-agonist norepinephrine (NOR). In the control and nutrition groups, HDBR increased heart rate (HR) and reduced stroke volume (SV), and there was a significantly greater increase in HR with ISO after HDBR. In contrast, the HR and SV of the exercise group were unchanged from pre-HDBR. After HDBR, leg vascular resistance (LVR) was greater than pre-HDBR in the exercise group but reduced in control and nutrition. LVR was reduced with ISO and increased with NOR. Changes in total peripheral resistance were similar to those of LVR but of smaller magnitude, perhaps because changes in cerebrovascular resistance index were directionally opposite to those of LVR. There were no changes in sensitivity of the vascular resistance responses to adrenergic stimulation. The HR response might reflect a change in sensitivity or a necessary response to the reduction in SV after HDBR in control and nutrition groups. The reduced peripheral vascular resistance after HDBR might help to explain orthostatic intolerance in women. Exercise was an effective countermeasure to the HDBR effects.

Edgell H, Grinberg A, Gagné N, Beavers KR, Hughson RL. Cardiovascular responses to lower body negative pressure before and after 4 h of head-down bed rest and seated control in men and women. J Appl Physiol 113: 1604 -1612, 2012. First published September 13, 2012 doi:10.1152/japplphysiol.00670.2012.-Cardiovascular deconditioning after a 4-h head-down bed rest (HDBR) might be a consequence of the time of day relative to pre-HDBR testing, or simply 4 h of confinement and inactivity rather than the posture change. Ten men and 11 women were studied during lower body negative pressure (LBNP) before and after 4-h HDBR and 4-h seated posture (SEAT) as a control for time of day and physical inactivity effects to test the hypotheses that cardiovascular deconditioning was a consequence of the HDBR posture, and that women would have a greater deconditioning response. Following HDBR, men and women had lower blood volume, higher heart rate with a greater increase during LBNP, a greater decrease of stroke volume during LBNP, lower central venous pressure, smaller inferior vena cava diameter, higher portal vein resistance index with a greater increase during LBNP, but lower forearm vascular resistance, lower norepinephrine, and lower renin. Women had lower vasopressin and men had higher vasopressin after HDBR, and women had lower pelvic impedance and men higher pelvic impedance. Following SEAT, brachial vascular resistance was reduced, thoracic impedance was elevated, the reduction of central venous pressure during LBNP was changed, women had higher angiotensin II whereas men had lower levels, and pelvic impedance increased in women and decreased in men. Cardiovascular deconditioning was greater after 4-h HDBR than after SEAT. Women and men had similar responses for most cardiovascular variables in the present study that tested the responses to LBNP after short-duration HDBR compared with a control condition. cardiovascular deconditioning; orthostatic challenge; sex differences; regional blood flow HEAD-DOWN BED REST (HDBR), as short as 4 h, is used as a simulation of microgravity exposure (6, 13). The body adapts quickly to this change in posture and reveals cardiovascular deconditioning that is characterized by elevations in heart rate (HR) and altered hormonal responses during application of lower body negative pressure (LBNP; i.e., lower baseline renin and angiotensin II which increased more in response to LBNP) (13) and by dramatic reduction in tolerance to an upright tilt (6). Thus acute alterations in the normal gravitational loading of the body appear to induce changes in the normal regulation of arterial blood pressure in the upright posture (13,19,35). But whether the changes during an orthostatic challenge after 4-h HDBR are an effect of the change in gravitational loading of the cardiovascular system or simply an effect of time of day and/or confinement has not been examined.Inherent in 4-h HDBR studies is the comparison of responses at different times of day for pre-vs. post-HDBR measurements. Several studies ha...