Hardikkumar M. Patel

Effect of healthy aging on renal vascular responses to local cooling and apnea.

Sympathetically mediated renal vasoconstriction may contribute to the pathogenesis of hypertension in older adults, but empirical data in support of this concept are lacking. In 10 young (26 ± 1 yr) and 11 older (67 ± 2 yr) subjects, we quantified acute hemodynamic responses to three sympathoexcitatory stimuli: local cooling of the forehead, cold pressor test (CPT), and voluntary apnea. We hypothesized that all stimuli would increase mean arterial blood pressure (MAP) and renal vascular resistance index (RVRI) and that aging would augment these effects. Beat-by-beat MAP, heart rate (HR), and renal blood flow velocity (from Doppler) were measured in the supine posture, and changes from baseline were compared between groups. In response to 1°C forehead cooling, aging was associated with an augmented MAP (20 ± 3 vs. 6 ± 2 mmHg) and RVRI (35 ± 6 vs. 16 ± 9%) but not HR. In older adults, there was a positive correlation between the cold-induced pressor response and forehead pain (R = 0.726), but this effect was not observed in young subjects. The CPT raised RVRI in both young (56 ± 13%) and older (45 ± 8%) subjects, but this was not different between groups. Relative to baseline, end-expiratory apnea increased RVRI to a similar extent in both young (46 ± 14%) and older (41 ± 9%) subjects. During sympathetic activation, renal vasoconstriction occurred in both groups. Forehead cooling caused an augmented pressor response in older adults that was related to pain perception.

Cardiac mechanics are impaired during fatiguing exercise and cold pressor test in healthy older adults.

We sought to determine how the aging left ventricle (LV) responds to sympathetic nervous system (SNS) activation. Three separate echocardiographic experiments were conducted in 11 healthy young (26 ± 1 yr) and 11 healthy older (64 ± 1 yr) adults. Tissue Doppler imaging was used to measure systolic myocardial velocity (S(m)), early diastolic myocardial velocity (E(m)), and late diastolic myocardial velocity (A(m)) during isometric fatiguing handgrip (IFHG), a 2-min cold pressor test (CPT), and 5 min of normobaric hypoxia. Heart rate (HR) and mean arterial pressure (MAP) were also monitored on a beat-by-beat basis; rate pressure product (RPP) was used as an index of myocardial oxygen demand. At peak IFHG, the groups had similar increases in RPP, but the ΔS(m) was significantly greater (i.e., larger impairment) in the older subjects (-0.82 ± 0.13 cm/s) compared with the young subjects (0.37 ± 0.30 cm/s). At peak IFHG, the ΔE(m) was similar between older (-1.59 ± 0.68 cm/s) and young subjects (-1.06 ± 0.76 cm/s). In response to the CPT, both S(m) and E(m) were reduced in the older adults but did not change relative to baseline in the young subjects. Normobaric hypoxia elevated HR and RPP in both groups but did not alter Tissue Doppler parameters. These data indicate that S(m) and E(m) are reduced in healthy older adults during IFHG and CPT. We speculate that suboptimal LV adaptations to SNS stress may partly explain why acute heavy exertion can trigger myocardial ischemia.

Sex differences in forearm vasoconstrictor response to voluntary apnea

Clinical evidence indicates that obstructive sleep apnea is more common and more severe in men compared with women. Sex differences in the vasoconstrictor response to hypoxemia-induced sympathetic activation might contribute to this clinical observation. In the current laboratory study, we determined sex differences in the acute physiological responses to maximal voluntary end-expiratory apnea (MVEEA) during wakefulness in healthy young men and women (26 ± 1 yr) as well as healthy older men and women (64 ± 2 yr). Mean arterial pressure (MAP), heart rate (HR), brachial artery blood flow velocity (BBFV, Doppler ultrasound), and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were measured, and changes in physiological parameters from baseline were compared between groups. The breath-hold duration and oxygen-saturation nadir were similar between groups. In response to MVEEA, young women had significantly less forearm vasoconstriction compared with young men (ΔBBFV: 2 ± 7 vs. -25 ± 6% and ΔCVC: -5 ± 4 vs. -31 ± 4%), whereas ΔMAP (12 ± 2 vs. 16 ± 3 mmHg) and ΔHR (4 ± 2 vs. 6 ± 3 bpm) were comparable between groups. The attenuated forearm vasoconstriction in young women was not observed in postmenopausal women (ΔBBFV -21 ± 5%). We concluded that young women have blunted forearm vasoconstriction in response to MVEEA compared with young men, and this effect is not evident in older postmenopausal women. These data suggest that female sex hormones dampen neurogenic vasoconstriction in response to apnea-induced hypoxemia.

β-Adrenergic blockade enhances coronary vasoconstrictor response to forehead cooling.

Forehead cooling activates the sympathetic nervous system and can trigger angina pectoris in susceptible individuals. However, the effect of forehead cooling on coronary blood flow velocity (CBV) is not well understood. In this human experiment, we tested the hypotheses that forehead cooling reduces CBV (i.e., coronary vasoconstriction) and that this vasoconstrictor effect would be enhanced under systemic β-adrenergic blockade. A total of 30 healthy subjects (age range, 23-79 years) underwent Doppler echocardiography evaluation of CBV in response to 60 s of forehead cooling (1°C ice bag on forehead). A subset of subjects (n = 10) also underwent the procedures after an intravenous infusion of propranolol. Rate pressure product (RPP) was used as an index of myocardial oxygen demand. Consistent with our first hypothesis, forehead cooling reduced CBV from 19.5 ± 0.7 to 17.5 ± 0.8 cm/s (P < 0.001), whereas mean arterial pressure increased by 11 ± 2 mmHg (P < 0.001). Consistent with our second hypothesis, forehead cooling reduced CBV under propranolol despite a significant rise in RPP. The current studies indicate that forehead cooling elicits a sympathetically mediated pressor response and a reduction in CBV, and this effect is augmented under β-blockade. The results are consistent with sympathetic activation of β-receptor coronary vasodilation in humans, as has been demonstrated in animals.

Ascorbic acid does not enhance hypoxia‐induced vasodilation in healthy older men

In response to hypoxia, a net vasodilation occurs in the limb vasculature in young healthy humans and this is referred to as “hypoxia‐induced vasodilation”. We performed two separate experiments to determine (1) if hypoxia‐induced forearm vasodilation is impaired in older men (n = 8) compared to young men (n = 7) and (2) if acute systemic infusion of ascorbic acid would enhance hypoxia‐induced vasodilation in older men (n = 8). Heart rate, mean arterial pressure, oxygen saturation, minute ventilation, forearm vascular conductance (FVC, Doppler ultrasound), and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were recorded continuously while subjects breathed 10% oxygen for 5 min. Changes from baseline were compared between groups and between treatments. The older adults had a significantly attenuated increase in FBF (13 ± 4 vs. 30 ± 7%) and FVC (16 ± 4 vs. 30 ± 7%) in response to 5 min of hypoxia. However, skin blood flow responses were comparable between groups (young: 35 ± 9, older: 30 ± 6%). In Experiment 2, FVC responses to 5 min of breathing 10% oxygen were not significantly different following saline (3 ± 10%) and ascorbic acid (8 ± 10%) in the older men. Ascorbic acid also had no physiological effects in the young men. These findings advance our basic understanding of how aging influences vascular responses to hypoxia and suggest that, in healthy humans, hypoxia‐induced vasodilation is not restrained by reactive oxygen species.

Forearm vascular responses to mental stress in healthy older adults

Forearm vascular conductance (FVC) increases in response to mental stress (verbal mental arithmetic) in young people. However, the effect of healthy aging and mental stress on FVC is unknown. In this study, we tested the hypothesis that FVC and cutaneous vascular conductance (CVC) would be attenuated in older adults compared to young adults. In 13 young (27 ± 1 year) and 11 older (62 ± 1 year) subjects, we quantified heart rate (HR), mean arterial pressure (MAP), FVC (Doppler ultrasound), and CVC (laser Doppler flowmetry) in response to a 3‐min bout of mental stress in the supine posture. Changes from baseline were compared between groups and physiological variables were also correlated. Older adults had a blunted HR response to mental stress (Δ = 7 ± 2 vs. 14 ± 2 beats/min) but ΔMAP was comparable between groups (Δ = 11 ± 2 mmHg vs. 9 ± 1). During the third minute of mental stress, the %ΔFVC (−2 ± 5 vs. 31 ± 12%) and %ΔCVC (2 ± 6 vs. 31 ± 15%) were both impaired in older adults compared to young subjects. There was no relationship between ΔHR and %ΔCVC in either group, but there was a positive relationship between ΔHR and %ΔFVC in both young subjects (R = 0.610, P < 0.027) and older subjects (R = 0.615, P < 0.044), such that larger tachycardia was associated with higher forearm vasodilation. These data indicate that older adults have impaired forearm vasodilation in response to mental stress.

Ascorbic acid attenuates the pressor response to voluntary apnea in postmenopausal women

We recently demonstrated that postmenopausal women have an augmented blood pressure response to voluntary apnea compared to premenopausal women. Both obstructive sleep apnea (OSA) and healthy aging are associated with increased oxidative stress, which may impair cardiovascular function. Restoring physiological responses could have clinical relevance since transient surges in blood pressure are thought to be an important stimulus for end‐organ damage in aging and disease. We tested the hypothesis that acute antioxidant infusion improves physiological responses to voluntary apnea in healthy postmenopausal women (n = 8, 64 ± 2 year). We measured beat‐by‐beat mean arterial pressure (MAP), heart rate (HR), and brachial artery blood flow velocity (BBFV, Doppler ultrasound) following intravenous infusion of normal saline and ascorbic acid (~3500 mg). Subjects performed maximal voluntary end‐expiratory apneas and changes (Δ) from baseline were compared between infusions. The breath hold duration and oxygen saturation nadir were similar between saline (29 ± 6 sec, 94 ± 1%) and ascorbic acid (29 ± 5 sec, 94 ± 1%). Ascorbic acid attenuated the pressor response to voluntary apnea (ΔMAP: 6 ± 2 mmHg) as compared to saline (ΔMAP: 12 ± 2 mmHg, P = 0.034) and also attenuated forearm vasoconstriction (ΔBBFV: 4 ± 9 vs. −12 ± 7%, P = 0.049) but did not affect ΔHR. We conclude that ascorbic acid lowers the blood pressure response to voluntary apnea in postmenopausal women by inhibiting vasoconstriction in the limb vasculature. Whether ascorbic acid has similar effects in OSA patients remains to be prospectively tested.