Sympathetic activity and baroreflex sensitivity in young women taking oral contraceptives.

BACKGROUND: We tested sympathetic and cardiovagal baroreflex sensitivity during the placebo or "low-hormone" phase (LH) and 2 to 3 weeks later during the "high-hormone" phase (HH) of oral contraceptive (OC) use in 9 women. METHODS AND RESULTS: Sympathetic baroreflex sensitivity was assessed by intravenous doses of sodium nitroprusside and phenylephrine and defined as the slope relating muscle sympathetic nerve activity (by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. No difference was observed for resting muscle sympathetic nerve activity or plasma norepinephrine levels. However, sympathetic baroreflex sensitivity was greater and mean arterial pressure was higher during the LH than in the HH phase. Similarly, cardiovagal baroreflex sensitivity was greater in the LH than in the HH phase. CONCLUSIONS: Sympathetic and cardiovagal baroreflex sensitivities change during the 28-day course of OC use. Furthermore, changes in baroreflex sensitivity with OC differ from changes in baroreflex sensitivity during the normal menstrual cycle.

Influence of the menstrual cycle on sympathetic activity, baroreflex sensitivity, and vascular transduction in young women.

BACKGROUND: Our goal was to test sympathetic and cardiovagal baroreflex sensitivity and the transduction of sympathetic traffic into vascular resistance during the early follicular (EF) and midluteal (ML) phases of the menstrual cycle. METHODS AND RESULTS: Sympathetic baroreflex sensitivity was assessed by lowering and raising blood pressure with intravenous bolus doses of sodium nitroprusside and phenylephrine. It was defined as the slope relating muscle sympathetic nerve activity (MSNA; determined by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. Vascular transduction was evaluated during ischemic handgrip exercise and postexercise ischemia, and it was defined as the slope relating MSNA and calf vascular resistance (determined by plethysmography). Resting MSNA (EF, 1170+/-151 U/min; ML, 2252+/-251 U/min; P<0.001) and plasma norepinephrine levels (EF, 240+/-21 pg/mL; ML, 294+/-25 pg/mL; P=0. 025) were significantly higher in the ML than in the EF phase. Furthermore, sympathetic baroreflex sensitivity was greater during the ML than the EF phase in every subject (MSNA/diastolic blood pressure slopes: EF, -4.15; FL, -5.42; P=0.005). No significant differences in cardiovagal baroreflex sensitivity or vascular transduction were observed. CONCLUSIONS: The present study suggests that the hormonal fluctuations that occur during the normal menstrual cycle may alter sympathetic outflow but not the transduction of sympathetic activity into vascular resistance.

Basal forebrain malformation with hyperhidrosis and hypothermia: variant of Shapiro's syndrome.

A 62-year-old woman presented with episodic sweating and shivering with reduced core temperature. Brain MRI demonstrated a basal forebrain malformation. Physiologic testing included EEG, SPECT, heat challenge, and autonomic testing. Glycopyrrolate aborted spells and raised core temperature. Hypothalamic dysregulation is likely the primary pathophysiology in the setting of other forebrain anomalies. These findings expand the structural abnormalities and treatment options within the temperature dysregulating conditions of Shapiro's syndrome and "diencephalic epilepsy."

Segregated signal averaging of sympathetic baroreflex responses in humans.

The goal of this study was to merge the methods currently used to assess beat-by-beat changes in muscle sympathetic nerve activity with a signal-averaging approach and overcome the inherent subjectivity and time-consuming nature of manual analysis of baroreflex-mediated sympathetic responses in humans. This is a retrospective study using data obtained during two prior studies [J. R. Halliwill, J. A. Taylor, and D. L. Eckberg. J. Physiol. (Lond.) 495: 279-288, 1996; C. T. Minson, J. R. Halliwill, T. Young, and M. J. Joyner. FASEB J. 13: A1044, 1999]. Beat-by-beat arterial pressure (Finapres device) and muscle sympathetic nerve activity (microneurography) were recorded in seven healthy, nonsmoking, normotensive subjects (2 men, 5 women) between the ages of 23 and 32 yr during arterial pressure changes induced by bolus injections of nitroprusside and phenylephrine. The muscle sympathetic nerve activity-diastolic pressure relationship was analyzed by both the traditional manual detection method and a novel segregated signal-averaging method. The results show the two analysis approaches are highly correlated across subjects (r = 0.914, P < 0. 05) and are in close agreement [slope for manual detection -6.17 +/- 0.91 (SE) vs. slope for segregated signal averaging -5.98 +/- 0.83 total integrated activity. beat(-1). mmHg(-1); P = 0.60]. However, a considerable time savings is seen with the new method (min vs. h). Segregated signal averaging as developed here provides a valid alternative to "by-hand" analysis of beat-by-beat changes in muscle sympathetic nerve activity that occur during dynamic baroreflex-mediated changes in sympathetic outflow. This approach provides an objective, rapid method to analyze nerve recordings.

Effect of systemic nitric oxide synthase inhibition on postexercise hypotension in humans.

An acute bout of aerobic exercise results in a reduced blood pressure that lasts several hours. Animal studies suggest this response is mediated by increased production of nitric oxide. We tested the extent to which systemic nitric oxide synthase inhibition [N(G)-monomethyl-L-arginine (L-NMMA)] can reverse the drop in blood pressure that occurs after exercise in humans. Eight healthy subjects underwent parallel experiments on 2 separate days. The order of the experiments was randomized between sham (60 min of seated upright rest) and exercise (60 min of upright cycling at 60% peak aerobic capacity). After both sham and exercise, subjects received, in sequence, systemic alpha-adrenergic blockade (phentolamine) and L-NMMA. Phentolamine was given first to isolate the contribution of nitric oxide to postexercise hypotension by preventing reflex changes in sympathetic tone that result from systemic nitric oxide synthase inhibition and to control for alterations in resting sympathetic activity after exercise. During each condition, systemic and regional hemodynamics were measured. Throughout the study, arterial pressure and vascular resistances remained lower postexercise vs. postsham despite nitric oxide synthase inhibition (e.g., mean arterial pressure after L-NMMA was 108.0+/-2.4 mmHg postsham vs. 102.1+/-3.3 mmHg postexercise; P<0.05). Thus it does not appear that postexercise hypotension is dependent on increased production of nitric oxide in humans.

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 (Deltalimb volume) = beta(0) + beta(1). (cuff pressure) + beta(2). (cuff pressure)(2), where Delta 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.

Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm.

We investigated the separate and combined contributions of nitric oxide (NO) and vasodilating prostaglandins as mediators of reactive hyperemia in the human forearm. Forearm blood flow (FBF) was measured with venous occlusion plethysmography after 5 min of ischemia. In one protocol (n = 12), measurements were made before and after intra-arterial administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) to one forearm. In a separate protocol (n = 7), measurements were made before and after systemic administration of the cyclooxygenase inhibitor ibuprofen and again after L-NMMA. L-NMMA reduced baseline FBF at rest (2.7 +/- 0.4 to 1.6 +/- 0.2 ml.100 ml-1.min-1; P < 0.05) and had a modest effect on peak forearm vascular conductance and flow (forearm vascular conductance = 31.1 +/- 3.1 vs. 25.7 +/- 2.5 ml.min-1.100 ml forearm-1.100 mmHg of perfusion pressure-1.min-1, P < 0.05; FBF = 26.6 +/- 2.9 vs. 22.8 +/- 2.6 ml.100 ml-1.min-1, P = 0.055). Total excess flow above baseline during reactive hyperemia was unaffected by L-NMMA (14.3 +/- 3.0 vs. 13.1 +/- 2.4 ml/100 ml; P < 0.05). Ibuprofen did not change FBF at rest, reduced peak FBF from 27.6 +/- 1.9 to 20.3 +/- 2.7 ml.100 ml-1.min-1 (P < 0.05), but had no effect on total excess flow above baseline, Infusion of L-NMMA after ibuprofen reduced FBF at rest by 40%, had no effect on peak flow, but reduced total excess flow above baseline from 12.0 +/- 2.5 to 7.6 +/- 1.3 ml/100 ml (P < 0.05). These date demonstrate that NO synthase inhibition has a modest effect on peak vasodilation during reactive hyperemia but plays a minimal role later. Prostaglandins appear to be important determinants of peak flow. The effects of NO synthase inhibition during reactive hyperemia may also be potentiated by concurrent cyclooxygenase inhibition.

Peak calf blood flow estimates are higher with Dohn than with Whitney plethysmograph.

Estimates of calf blood flow with venous occlusion plethysmography vary widely between studies, perhaps due to the use of different plethysmographs. Consequently, we compared calf blood flow estimates at rest and during reactive hyperemia in eight healthy subjects (four men and four women) with two commonly used plethysmographs: the mercury-in-silastic (Whitney) strain gauge and Dohn air-filled cuff. To minimize technical variability, flow estimates were compared with a Whitney gauge and a Dohn cuff on opposite calves before and after 10 min of bilateral femoral arterial occlusion. To account for any differences between limbs, a second trial was conducted in which the plethysmographs were switched. Resting flows did not differ between the plethysmographs (P = 0.096), but a trend toward lower values with the Whitney was apparent. Peak flows averaged 37% lower with the Whitney (27.8 +/- 2.8 ml.dl-1.min-1) than with the Dohn plethysmograph (44.4 +/- 2.8 ml.dl-1.min-1; P < 0.05). Peak flow expressed as a multiple above baseline was also lower with the Whitney (10-fold) than with the Dohn plethysmograph (14.5-fold; P = 0.02). Across all flows at rest and during reactive hyperemia, estimates were highly correlated between the plethysmographs in all subjects (r2 = 0.96-0.99). However, the mean slope for the Whitney-Dohn relationship was only 60 +/- 2%, indicating that over a wide range of flows the Whitney gauge estimate was 40% lower than that for the Dohn cuff. These results demonstrate that the same qualitative results can be obtained with either plethysmograph but that absolute flow values will generally be lower with Whitney gauges.

Reflex responses to regional venous pooling during lower body negative pressure in humans.

Lower body negative pressure is frequently used to simulate orthostasis. Prior data suggest that venous pooling in abdominal or pelvic regions may have major hemodynamic consequences. Therefore, we developed a simple paradigm for assessing regional contributions to venous pooling during lower body negative pressure. Sixteen healthy men and women underwent graded lower body negative pressure protocols to 60 mmHg while wearing medical anti-shock trousers to prevent venous pooling under three randomized conditions: 1) no trouser inflation (control), 2) only the trouser legs inflated, and 3) the trouser legs and abdominopelvic region inflated. Without trouser inflation, heart rate increased 28 +/- 4 beats/min, mean arterial pressure fell -3 +/- 2 mmHg, and forearm vascular resistance increased 51 +/- 9 units at 60 mmHg lower body negative pressure. With inflation of either the trouser legs or the trouser legs and abdominopelvic region, heart rate and mean arterial pressure did not change during lower body negative pressure. By contrast, although the forearm vasoconstrictor response to lower body negative pressure was attenuated by inflation of the trouser legs (delta forearm vascular resistance 33 +/- 10 units, P < 0.05 vs. control), attenuation was greater with the inflation of the trouser legs and abdominopelvic region (delta forearm vascular resistance 16 +/- 5 units, P < 0.05 vs. control and trouser legs-only inflation). Thus the hemodynamic consequences of pooling in the abdominal and pelvic regions during lower body negative pressure appear to be less than in the legs in healthy individuals.

Leg mass and lower body negative pressure tolerance in men and women.

To explore the hypothesis that lower body muscle mass correlates with orthostatic tolerance, 18 healthy volunteers (age 18-48 yr; 10 men, 8 women) underwent a graded lower body negative pressure (LBNP) protocol consisting of six, 5-min stages of suction up to 60 mmHg in 10-mmHg increments. Forearm blood flow, heart rate, and blood pressure were measured, and forearm vascular resistance was calculated. Leg muscle mass was assessed by dual-energy X-ray absorptiometry. All subjects received standard intravenous hydration for at least 8 h before the study. Six men and four women completed all stages of LBNP. Four men and four women developed presyncopal symptoms, including marked bradycardia and/or hypotension, at LBNP levels of 30 mmHg (n = 2;1 man, 1 woman), 40 mmHg (n = 2;1 man, 1 woman), and 50 mmHg (n = 4;2 men, 2 women). The presyncopal subjects had leg muscle masses ranging from 19.5 to 25.2 kg in men and from 11.7 to 16.6 kg in women. In subjects who completed all stages of LBNP, leg muscle mass ranged from 17.5 to 24.1 kg in men and from 10.4 to 18.0 kg in women. Leg muscle mass did not differ between presyncopal subjects and those who completed the protocol. Furthermore, there were no differences in the hemodynamic responses to LBNP between subjects with low vs. high leg mass. These data suggest that leg muscle mass is not a critical determinant of LBNP tolerance in otherwise healthy men and women.

Effects of nitric oxide synthase inhibition on cutaneous vasodilation during body heating in humans.

We sought to examine further the potential role of nitric oxide (NO) in the neurally mediated cutaneous vasodilation in nonacral skin during body heating in humans. Six subjects were heated with a water-perfused suit while cutaneous blood flow was measured by using laser-Doppler flowmeters placed on both forearms. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) was given selectively to one forearm via a brachial artery catheter after marked cutaneous vasodilation had been established. During body heating, oral temperature increased by 1.1 +/- 0.1 degreesC while heart rate increased by 30 +/- 6 beats/min. Mean arterial pressure stayed constant at 84 +/- 2 mmHg. In the experimental forearm, cutaneous vascular conductance (CVC; laser-Doppler) decreased to 86 +/- 5% of the peak response to heating (P < 0.05 vs. pre-L-NMMA values) after L-NMMA infusion. In some subjects, L-NMMA caused CVC to fall by approximately 30%; in others, it had little impact on the cutaneous circulation. CVC in the control arm showed a similar increase with heating, then stayed constant while L-NMMA was given to the contralateral side. These results demonstrate that NO contributes modestly, but not consistently, to cutaneous vasodilation during body heating in humans. They also indicate that NO is not the only factor responsible for the dilation.

beta-Receptor agonist activity of phenylephrine in the human forearm.

Phenylephrine is generally regarded as a "pure" alpha(1)-agonist. However, after treatment of the forearm with the alpha-adrenergic-blocking drug phentolamine, brachial artery infusion of phenylephrine can cause transient forearm vasodilation. To determine whether this response was beta-receptor mediated, phenylephrine, phentolamine, and propranolol were infused into the brachial arteries of six healthy volunteers. Forearm vascular conductance (FVC) was also calculated and expressed as arbitrary units (units). Infusion of phenylephrine by itself (0.5 microg. dl forearm volume(-1). min(-1)) caused a sustained decrease (P < 0.05) in FVC from 3.5 +/- 0.7 to 0.9 +/- 0.2 units (P < 0.05). Infusion of the alpha-blocker phentolamine increased (P < 0.05) baseline FVC to 5.7 +/- 1.3 units. Subsequent infusion of phenylephrine after alpha-blockade caused FVC to increase (P < 0.05) for ~1 min from 5.7 +/- 1.3 to a peak of 13.1 +/- 1.8 units. Propranolol had no effect on baseline flow, and subsequent phenylephrine infusion after alpha- and beta-blockade caused a small, but significant, sustained decrease in FVC from 5.1 +/- 1.0 to 3.6 +/- 0.8 units. There were no systemic effects from the infusions, and saline infusion at the same rate (1-2 ml/min) had no forearm vasoconstrictor or dilator effects. These data indicate that in humans phenylephrine can exert transient beta(2)-vasodilator activity when its predominant alpha-constrictor effects are blocked.

Sympathetic withdrawal and forearm vasodilation during vasovagal syncope in humans.

Our aim was to determine whether sympathetic withdrawal alone can account for the profound forearm vasodilation that occurs during syncope in humans. We also determined whether either vasodilating beta 2-adrenergic receptor or nitric oxide (NO) contributes to this dilation. Forearm blood flow was measured bilaterally in healthy volunteers (n = 10) by using plethysmography during two bouts of graded lower body negative pressure (LBNP) to syncope. In one forearm, drugs were infused via a brachial artery catheter while the other forearm served as a control. In the control arm, forearm vascular resistance (FVR) increased from 77 +/- 7 units at baseline to 191 +/- 36 units with -40 mmHg of LBNP (P < 0.05). Mean arterial pressure fell from 94 +/- 2 to 47 +/- 4 mmHg just before syncope, and all subjects demonstrated sudden bradycardia at the time of syncope. At the onset of syncope, there was sudden vasodilation and FVR fell to 26 +/- 6 units (P < 0.05 vs. baseline). When the experimental forearm was treated with bretylium, phentolamine, and propranolol, baseline FVR fell to 26 +/- 2 units, the vasoconstriction during LBNP was absent, and FVR fell further to 16 +/- 1 units at syncope (P < 0.05 vs. baseline). During the second trial of LBNP, mean arterial pressure again fell to 47 +/- 4 mmHg and bradycardia was again observed. Treatment of the experimental forearm with the NO synthase inhibitor NG-monomethyl-L-arginine in addition to bretylium, phentolamine, and propranolol significantly increased baseline FVR to 65 +/- 5 units but did not prevent the marked forearm vasodilation during syncope (FVR = 24 +/- 4 vs. 29 +/- 8 units in the control forearm). These data suggest that the profound vasodilation observed in the human forearm during syncope is not mediated solely by sympathetic withdrawal and also suggest that neither beta 2-adrenergic-receptor-mediated vasodilation nor NO is essential to observe this response.

Influence of age and gender on cardiac output-VO2 relationships during submaximal cycle ergometry.

It is presently unclear how gender, aging, and physical activity status interact to determine the magnitude of the rise in cardiac output (Qc) during dynamic exercise. To clarify this issue, the present study examined the Qc-O2 uptake (Vo2) relationship during graded leg cycle ergometry in 30 chronically endurance-trained subjects from four groups (n = 6-8/group): younger men (20-30 yr), older men (56-72 yr), younger women (24-31 yr), and older women (51-72 yr). Qc (acetylene rebreathing), stroke volume (Qc/heart rate), and whole body Vo2 were measured at rest and during submaximal exercise intensities (40, 70, and approximately 90% of peak Vo2). Baseline resting levels of Qc were 0.6-1.2 l/min less in the older groups. However, the slopes of the Qc-Vo2 relationship across submaximal levels of cycling were similar among all four groups (5.4-5.9 l/l). The absolute Qc associated with a given Vo2 (1.0-2.0 l/min) was also similar among groups. Resting and exercise stroke volumes (ml/beat) were lower in women than in men but did not differ among age groups. However, older men and women showed a reduced ability, relative to their younger counterparts, to maintain stroke volume at exercise intensities above 70% of peak Vo2. This latter effect was most prominent in the oldest women. These findings suggest that neither age nor gender has a significant impact on the Qc-Vo2 relationships during submaximal cycle ergometry among chronically endurance-trained individuals.

Effects of acetylcholine and nitric oxide on forearm blood flow at rest and after a single muscle contraction.

We tested the hypothesis that ACh or nitric oxide (NO) might be involved in the vasodilation that accompanies a single contraction of the forearm. Eight adults (3 women and 5 men) completed single 1-s-duration contractions of the forearm to raise and lower a weight equivalent to approximately 20% maximal voluntary contraction through a distance of 5 cm. In a second protocol, each subject had a cuff, placed completely about the forearm, inflated to 120 mmHg for a 1-s period, then released as a simulation of the mechanical effect of muscle contraction. Three conditions were studied, always in this order: 1) control, with intra-arterial infusion of saline; 2) after muscarinic blockade with atropine; and 3) after NO synthase inhibition with NG-monomethyl-L-arginine (L-NMMA) plus atropine. Forearm blood flow (FBF), measured by combined pulsed and echo Doppler ultrasound, was reduced at rest with L-NMMA-atropine compared with the other two conditions. After the single contraction, there were no effects of atropine, but L-NMMA reduced the peak FBF and the total postcontraction hyperemia. After the single cuff inflation, atropine had no effects, whereas L-NMMA caused changes similar to those seen after contraction, reducing the peak FBF and the total hyperemia. The observation that L-NMMA reduced FBF in response to both cuff inflation and a brief contraction indicates that NO from the vascular endothelium might modulate the basal level of vascular tone and the mechanical component of the hyperemia with exercise. It is unlikely that ACh and NO from the endothelium are involved in the dilator response to a single muscle contraction.

No effect of systemic isocapnic hypoxia on α-adrenergic vasoconstrictor responsiveness in human skin.

UNLABELLED: Hypoxia impairs body temperature regulation and abolishes the decline in skin temperature associated with cold exposure, suggesting that cutaneous vasoconstriction is impaired. AIM: The purpose of this study was to test the hypothesis that cutaneous vasoconstriction to intradermal tyramine, an index of post-junctional vasoconstrictor responsiveness, is reduced during hypoxia. METHODS: Twelve subjects (six males, six females) had three microdialysis fibres placed in the ventral forearm. Fibres received either lactated ringers, 5 mm yohimbine (α-adrenergic blockade), or 10.5 µm BIBP-3226 (to antagonize neuropeptide Y Y(1) receptors). Skin blood flow was assessed at each site (laser-Doppler flowmetry) and cutaneous vascular conductance (CVC) was calculated (red blood cell flux/mean arterial pressure) and scaled to baseline. Vasoconstrictor responses to tyramine (173 µm) were tested during normoxia and steady-state isocapnic hypoxia (SaO(2) = 80%) in random order. RESULTS: During normoxia, tyramine reduced CVC by 56.0±5.6 and 50.3±8.0% in control and BIBP-3226 sites (both P<0.05 vs. pre-tyramine; P=0.445 between sites) whereas CVC in the yohimbine site did not change (P=0.398 vs. pre-tyramine). During isocapnic hypoxia, tyramine reduced CVC by 55.9±5.1 and 54.2±5.4% in control and BIBP-3226 sites (both P<0.05 vs. pre-tyramine; P=0.814 between sites) whereas CVC was unchanged in the yohimbine site (P=0.732 vs. pre-tyramine). Isocapnic hypoxia did not affect vasoconstrictor responses at any site (all P>0.05 vs. normoxia). CONCLUSION: We conclude that post-junctional α-adrenergic vasoconstrictor responsiveness is not affected by hypoxia in non-acral skin.

Mechanisms and clinical implications of post-exercise hypotension in humans.

Post-exercise hypotension is common after moderate-intensity dynamic exercise. It results from persistent reductions in vascular resistance mediated by the autonomic nervous system and vasodilator substances. These effects appear more pronounced and last longer in hypertensive individuals. Post-exercise hypotension may also play an important role in plasma volume recovery after exercise.