John H. Eisenach

Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation

Large, reproducible interindividual differences exist in resting sympathetic nerve activity among normotensive humans with similar arterial pressures, resulting in a lack of correlation between muscle sympathetic nerve activity (MSNA) and arterial pressure among individuals. Although it is known that the arterial pressure is the main short‐term determinant of MSNA in humans via the arterial baroreflex, the lack of correlation among individuals suggests that the level of arterial pressure is not the only important input in regulation of MSNA in humans. We studied the relationship between cardiac output (CO) and baroreflex control of sympathetic activity by measuring MSNA (peroneal microneurography), arterial pressure (arterial catheter), CO (acetylene uptake technique) and heart rate (HR; electrocardiogram) in 17 healthy young men during 20 min of supine rest. Across individuals, MSNA did not correlate with mean or diastolic blood pressure (r < 0.01 for both), but displayed a significant negative correlation with CO (r=−0.71, P= 0.001). To assess whether CO is related to arterial baroreflex control of MSNA, we constructed a baroreflex threshold diagram for each individual by plotting the percentage occurrence of a sympathetic burst against diastolic pressure. The mid‐point of the diagram (T50) at which 50% of cardiac cycles are associated with bursts, was inversely related to CO (r=−0.75, P < 0.001) and stroke volume (SV) (r=−0.57, P= 0.015). We conclude that dynamic inputs from CO and SV are important in regulation of baroreflex control of MSNA in healthy, normotensive humans. This results in a balance between CO and sympathetically mediated vasoconstriction that may contribute importantly to normal regulation of arterial pressure in humans.

Sex Differences in Sympathetic Neural-Hemodynamic Balance Implications for Human Blood Pressure Regulation

Among young normotensive men, a reciprocal balance between cardiac output and sympathetic nerve activity is important in the regulation of arterial pressure. In young women, the balance among cardiac output, peripheral resistance, and sympathetic nerve activity is unknown. Consequently, the aim of this study was to examine the relationship of cardiac output and total peripheral resistance to muscle sympathetic nerve activity in young women. Multiunit peroneal recordings of muscle sympathetic nerve activity were obtained in 17 women (mean±SEM: age 24±3 years) and 21 men (mean±SEM: age 25±5 years). Mean resting muscle sympathetic nerve activity was lower in women compared with men (19±3 versus 25±1 bursts minute−1; P<0.05), as was mean arterial pressure (89±1 versus 94±2 mm Hg; P<0.05). Mean arterial pressure was not related to muscle sympathetic nerve activity in men (P=0.80) or women (P=0.62). There was a positive relationship between total peripheral resistance and muscle sympathetic nerve activity (r=0.62; P<0.05) and an inverse relationship between cardiac output and muscle sympathetic nerve activity (r=−0.69; P<0.05) in men. Unexpectedly, muscle sympathetic nerve activity had no relationship to either total peripheral resistance (r=−0.27; P>0.05) or cardiac output (r=0.23; P>0.05) in women. Our results demonstrate that men and women rely on different integrated physiological mechanisms to maintain a normal arterial pressure despite widely varying sympathetic nerve activity among individuals. These findings may have important implications for understanding how hypertension and other disorders of blood pressure regulation occur in men and women.

Hyperhidrosis: Evolving Therapies for a Well-Established Phenomenon

The socially embarrassing disorder of excessive sweating, or hyperhidrosis, and its treatment options are gaining widespread attention. In order of frequency, palmar-plantar, palmar-axillary, Isolated axillary, and cranlofacial hyperhidrosis are distinct disorders of sudomotor regulation. A common link among these disorders is an excessive, nonthermoregulatory sweat response often to emotional stimuli in body regions influenced by the anterior cingulate cortex as opposed to the thermoregulatory sweat response regulated by the preoptic-anterior hypothalamus. Diagnosis of these mechanistically ambiguous disorders is primarily from patient history and physical examination, whereas results of laboratory studies performed with indicator powder reveal the distribution and severity of resting hyperhidrosis and document the integrity of thermoregulatory sweating. Treatment options lie on a continuum based on the severity of hyperhidrosis and the risks and benefits of therapy. In general, therapy begins with antiperspirants or anticholinergics. Iontophoresis is available for palmar-plantar and axillary hyperhidrosis. Botulinum toxin type A or local excision/curettage is effective for isolated axillary hyperhidrosis not responsive to topical application of aluminum chloride. Endoscopic thoracic sympathectomy may be used for severe cases of palmar-plantar and palmar-axillary hyperhidrosis. No sole therapy of choice has emerged for craniofacial sweating. The long-term sequelae of hyperhidrosis and its treatment also are discussed.

Sex and ageing differences in resting arterial pressure regulation: the role of the β-adrenergic receptors

Non‐Technical Summary  In young men, sympathetic nerve activity is directly related to the level of vasoconstrictor tone in the peripheral vasculature. However, in young women this relationship does not exist, suggesting that certain factors (potentially related to the female sex hormones) offset the transfer of sympathetic nerve activity into vasoconstrictor tone in this population. In the present study we show that, in young women, the β‐adrenergic receptors (which cause vasodilatation in response to noradrenaline) blunt the vasoconstrictor effect of resting sympathetic nerve activity in young women. This mechanism does not occur in young men or postmenopausal women. It is possible that the β‐adrenergic receptors may partially protect young women against the sometimes harmful effects of high sympathetic nerve activity. This may explain why the risk of developing hypertension is greater in young men and postmenopausal women (who have very high sympathetic nerve activity) compared to young women.

Ageing reduces nitric-oxide- and prostaglandin-mediated vasodilatation in exercising humans

In older humans, infusions of endothelial agonists suggest endothelial dysfunction, due in part to less nitric oxide (NO)‐ and prostaglandin (PG)‐mediated vasodilatation, and a shift toward PG‐mediated vasoconstriction. Ageing can also be associated with lower exercise blood flow (exercise hyperaemia), but the vascular mechanisms mediating this remain unknown. Notably, in young adults, inhibition of NO and PGs during exercise decreases exercise hyperaemia by ∼20 and ∼12%, respectively. We tested our first hypothesis that in older humans inhibition of NO would decrease hyperaemia, but that inhibition of PGs would increase hyperaemia by blocking vasoconstrictor PGs. Fifteen older subjects (65 ± 3 years) performed dynamic forearm exercise for 20 min (20 contractions min−1). Forearm blood flow (FBF) was measured beat‐to‐beat with Doppler ultrasound, while saline or drugs were infused sequentially via brachial artery catheter in the exercising forearm. After achieving steady‐state exercise, l‐NAME (25 mg) was infused over 5 min to inhibit NO synthase. After a further 2 min of exercise (saline), ketorolac (6 mg) was infused over 5 min to inhibit PGs, followed by a futher 3 min of exercise with saline. Drug order was reversed in seven subjects. l‐NAME reduced steady‐state exercise hyperaemia by 12 ± 3% in older subjects (P < 0.01), whereas ketorolac had no net effect on blood flow (3 ± 6%, P > 0.4). The effects of l‐NAME and ketorolac were independent of drug order. By comparing these results with our previous results in young adults, we tested our second hypothesis that in older humans inhibition of NO or PGs would have less impact on exercise hyperaemia due to less vasodilatation from these signals. Our results suggest that, compared with young adults, in older humans the relative contribution of NO to exercise hyperaemia is reduced ∼45% (22 ± 4 versus 12 ± 3%), but the role of PG in mediating vasodilatation is lost in ageing human skeletal muscle. Lower exercise hyperaemia in older humans may be mediated in part by less NO‐ and PG‐mediated vasodilatation during exercise.

Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise

We tested the hypotheses that (1) nitric oxide (NO) contributes to augmented skeletal muscle vasodilatation during hypoxic exercise and (2) the combined inhibition of NO production and adenosine receptor activation would attenuate the augmented vasodilatation during hypoxic exercise more than NO inhibition alone. In separate protocols subjects performed forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n= 12), subjects received intra‐arterial administration of saline (control) and the NO synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA). In protocol 2 (n= 10), subjects received intra‐arterial saline (control) and combined l‐NMMA–aminophylline (adenosine receptor antagonist) administration. Forearm vascular conductance (FVC; ml min−1 (100 mmHg)−1) was calculated from forearm blood flow (ml min−1) and blood pressure (mmHg). In protocol 1, the change in FVC (Δ from normoxic baseline) due to hypoxia under resting conditions and during hypoxic exercise was substantially lower with l‐NMMA administration compared to saline (control; P < 0.01). In protocol 2, administration of combined l‐NMMA–aminophylline reduced the ΔFVC due to hypoxic exercise compared to saline (control; P < 0.01). However, the relative reduction in ΔFVC compared to the respective control (saline) conditions was similar between l‐NMMA only (protocol 1) and combined l‐NMMA–aminophylline (protocol 2) at 10% (−17.5 ± 3.7 vs.−21.4 ± 5.2%; P= 0.28) and 20% (−13.4 ± 3.5 vs.−18.8 ± 4.5%; P= 0.18) hypoxic exercise. These findings suggest that NO contributes to the augmented vasodilatation observed during hypoxic exercise independent of adenosine.

Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans

In humans, sympathetic nerve activity (SNA) at rest can vary several‐fold among normotensive individuals with similar blood pressures. We recently showed that a balance exists between SNA and cardiac output, which may contribute to the maintenance of normal blood pressures over the range of resting SNA levels. In the present studies, we assessed whether variability in vascular adrenergic responsiveness has a role in this balance. We tested the hypothesis that forearm vascular responses to noradrenaline (NA) and tyramine (TYR) are related to SNA such that individuals with lower resting SNA have greater adrenergic responsiveness, and vice‐versa. We measured multifibre muscle SNA (MSNA; microneurography), arterial pressure (brachial catheter) and forearm blood flow (plethysmography) in 19 healthy subjects at baseline and during intrabrachial infusions of NA and TYR. Resting MSNA ranged from 6 to 34 bursts min−1, and was inversely related to vasoconstrictor responsiveness to both NA (r= 0.61, P= 0.01) and TYR (r= 0.52, P= 0.02), such that subjects with lower resting MSNA were more responsive to NA and TYR. We conclude that interindividual variability in vascular adrenergic responsiveness contributes to the balance of factors that maintain normal blood pressure in individuals with differing levels of sympathetic neural activity. Further understanding of this balance may have important implications for our understanding of the pathophysiology of hypertension.

Influences of hydration on post‐exercise cardiovascular control in humans

Dehydration is known to decrease orthostatic tolerance and cause tachycardia, but little is known about the cardiovascular control mechanisms involved. To test the hypothesis that arterial baroreflex sensitivity increases during exercise‐induced dehydration, we assessed arterial baroreflex responsiveness in 13 healthy subjects (protocol 1) at baseline (PRE‐EX) and 1 h after (EX‐DEH) 90 min of exercise to cause dehydration, and after subsequent intravenous rehydration with saline (EX‐REH). Six of these subjects were studied a second time (protocol 2) with intravenous saline during exercise to prevent dehydration. We measured heart rate, central venous pressure and arterial pressure during all trials, and muscle sympathetic nerve activity (MSNA) during the post‐exercise trials. Baroreflex responses were assessed using sequential boluses of nitroprusside and phenylephrine (modified Oxford technique). After exercise in protocol 1 (EX‐DEH), resting blood pressure was decreased and resting heart rate was increased. Cardiac baroreflex gain, assessed as the responsiveness of heart rate or R‐R interval to changes in systolic pressure, was diminished in the EX‐DEH condition (9.17 ± 1.06 ms mmHg−1vs. PRE‐EX: 18.68 ± 2.22 ms mmHg−1, P < 0.05). Saline infusion after exercise did not alter the increase in HR post‐exercise or the decrease in baroreflex gain (EX‐REH: 10.20 ± 1.43 ms mmHg−1; P > 0.10 vs. EX‐DEH). Saline infusion during exercise (protocol 2) resulted in less of a post‐exercise decrease in blood pressure and a smaller change in cardiac baroreflex sensitivity. Saline infusion caused a decrease in MSNA in protocol 1. We conclude that exercise‐induced dehydration causes post‐exercise changes in the baroreflex control of blood pressure that may contribute to, rather than offset, orthostatic intolerance.

Aging Is Associated With Reduced Prostacyclin-Mediated Dilation in the Human Forearm

Aging is associated with reduced endothelial function. There is indirect evidence for reduced prostacyclin (PGI2)-mediated vasodilation with aging, but it is unknown whether this is because of reduced dilation to PGI2 or altered production. In addition, the contribution of endothelial NO to PGI2-mediated dilation is unknown. Using plethysmography to determine forearm blood flow, we studied the effect of PGI2 in 10 older (61 to 73 years) and 10 younger (19 to 45 years) subjects using 3 escalating intra-arterial doses of PGI2 (epoprostenol). PGI2 was also administered after NO synthase inhibition with NG-monomethyl-l-arginine acetate. The percent of change in forearm vascular conductance (mean±SEM) from baseline after PGI2 was significantly lower (P=0.002) in the aging individuals (52±11%, 164±23%, and 221±27% versus 115±20%, 249±19%, and 370±35%). In addition, the group-by-dose interaction was also significant (P=0.018). After NO synthase inhibition, the dose-response curve to PGI2 was blunted in the young subjects but unchanged in the older subjects; the difference between the groups was no longer significant. Our data suggest that the reduced dilator effects of PGI2 in older individuals are attributable to a reduction in the contribution of endothelial-derived NO versus alterations in the direct effects of PGI2 on vascular smooth muscle.

Age-Related Differences in the Sympathetic-Hemodynamic Balance in Men

As humans age, the tonic level of activity in sympathetic vasoconstrictor nerves increases and may contribute to age-related increases in blood pressure. In previous studies in normotensive young men with varying levels of resting sympathetic nerve activity, we observed a balance among factors contributing to blood pressure regulation, such that higher sympathetic activity was associated with lower cardiac output and lesser vascular responsiveness to &agr;-adrenergic agonists, which limited the impact of high sympathetic activity on blood pressure. In the present study, we tested the hypothesis that older normotensive men would exhibit a similar balance among these variables (sympathetic nerve activity, cardiac output, and &agr;-adrenergic responsiveness) but that this balance would be shifted toward higher sympathetic nerve activity values. We measured muscle sympathetic nerve activity, cardiac output, arterial pressure, and forearm vasoconstrictor responses in 17 older men and compared these with previous data collected in 14 younger men. Muscle sympathetic activity (burst incidence) was positively related to diastolic blood pressure in the older men (r=0.49; P=0.05); this relationship was not observed in young men. In addition, there was no relationship between cardiac output and muscle sympathetic activity (r=0.29; P>0.05) or between muscle sympathetic activity and vasoconstrictor responses in the older men (eg, norepinephrine: r=−0.21; P>0.05). Although our older subjects were normotensive, the relationship between muscle sympathetic nerve activity and diastolic blood pressure and the lack of “balance” among the other variables suggest that these changes with aging may contribute to the risk of sympathetically mediated hypertension in older humans.