Altered autonomic support of arterial blood pressure with age in healthy men.

BACKGROUND: Primary aging is associated with changes in the autonomic nervous system (ANS), but the functional significance of these changes for systemic circulatory control of arterial blood pressure (BP) is unknown. We tested the hypothesis that ANS support of BP is altered in healthy older humans. METHODS AND RESULTS: A total of 23 young (aged 24+/-1 years; systolic/diastolic BP, 126+/-2/66+/-1 mm Hg) and 16 older (aged 65+/-1 years; systolic/diastolic BP, 125+/-3/62+/-2 mm Hg) healthy men were studied before and during ganglionic blockade (intravenous trimethaphan). The reduction in mean BP (radial artery catheter) with trimethaphan was almost twice as great in the older men (-33+/-2 versus -19+/-2 mm Hg; -40% versus -22% of baseline; P<0.01) due to a lack of increase in heart rate (3+/-2 versus 25+/-2 bpm; P<0.001) and cardiac output (-0.42+/-0.19 versus 1.01+/-0.26 L/min; P<0.001); the decreases in systemic vascular resistance were not different. The absence of tachycardia in the older men was associated with reduced baseline heart rate variability (HRV, P<0.05); the change in heart rate with trimethaphan correlated with the standard deviation of the R-R intervals (HRV(SD R-R interval); r=0.57, P<0.001). Among individual subjects (pooled groups), the reductions in mean BP with trimethaphan were most strongly related to measures of sympathetic activity (r=0.58 to 0.67, P<0.005), change in mean BP with intravenous phenylephrine (r=0.57, P<0.001), and HRV(SD R-R interval) (r=-0.40, P<0.01). CONCLUSIONS: ANS support of BP is altered with age in healthy men due to less cardiac vagal inhibition of heart rate and cardiac output. Basal sympathetic activity and alpha-adrenergic vascular sensitivity are also key physiological correlates of ANS support of BP in healthy men.

Familial orthostatic tachycardia due to norepinephrine transporter deficiency.

UNLABELLED: Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

Multiple system atrophy: new developments in pathophysiology and therapy.

There have been substantial advances in the last five years in understanding the basic and clinical pathophysiology underlying multiple system atrophy (MSA). Identification of glial cytoplasmic inclusions has been the most important organizing principle for further elucidation of underlying mechanisms. Recently, several unexpected developments at the clinical level have been reported. In this article, we will focus on two of these: (1) the recognition that substantial autonomic function is retained in MSA but not modulated appropriately, and (2) a potent pressor effect from ingestion of water, which cannot be explained by currently understood physiologic and pathophysiologic mechanisms. In some patients, water has elicited a 50% increase in blood pressure and been more therapeutically effective than any available pressor drug. By careful coordination of the pressor effect of water and the depressor effect of carbohydrate-rich food, many patients with MSA can now have their blood pressure controlled without pharmacological intervention.

Severely impaired baroreflex-buffering in patients with monogenic hypertension and neurovascular contact.

BACKGROUND: We identified a family with a monogenic syndrome of hypertension, brachydactyly, and neurovascular contact of the brain stem. Neurovascular contact of the ventrolateral medulla may lead to arterial hypertension by interfering with baroreflex function. METHODS AND RESULTS: In 5 patients with monogenic hypertension (18 to 34 years old), we conducted detailed autonomic function tests. Blood pressure during complete ganglionic blockade was 134+/-4.9/82+/-4.1 mm Hg and 90+/-6/49+/-2.4 mm Hg in patients and in control subjects, respectively. During ganglionic blockade, plasma vasopressin concentration increased 24-fold in control subjects and <2-fold in patients. In patients, cold pressor testing, hand-grip testing, and upright posture all increased blood pressure excessively. In contrast, muscle sympathetic nerve activity was not increased at rest or during cold pressor testing. The phenylephrine dose that increased systolic blood pressure 12.5 mm Hg was 8.0+/-2.0 microg in patients and 135+/-35 microg in control subjects before ganglionic blockade and 5.4+/-0.4 microg in patients and 13+/-4.8 microg in control subjects during ganglionic blockade. CONCLUSIONS: In patients with monogenic hypertension and neurovascular contact, basal blood pressure was increased even during sympathetic and parasympathetic nerve traffic interruption. However, sympathetic stimuli caused an excessive increase in blood pressure. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that baroreflex buffering and baroreflex-mediated vasopressin release are severely impaired.

The neuropathic postural tachycardia syndrome.

BACKGROUND: The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. METHODS: We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. RESULTS: At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). CONCLUSIONS: The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.

Interaction of carbon dioxide and sympathetic nervous system activity in the regulation of cerebral perfusion in humans.

Recent studies suggest that activation of the sympathetic nervous system either directly or indirectly influences cerebrovascular tone in humans even within the autoregulatory range. In 6 healthy subjects (aged 29+/-4 years), we used transcranial Doppler sonography to determine cerebral blood flow velocity during sympathetic activation elicited through head-up tilt (HUT) and sympathetic deactivation through ganglionic blockade. PaCO(2) was manipulated through hyperventilation and CO(2) breathing (5%). With subjects in the supine position and during HUT, mean arterial pressure was not influenced by PaCO(2). During ganglionic blockade, mean arterial pressure decreased markedly with hyperventilation (-13+/-1.9 mm Hg). Manipulation of sympathetic tone elicited only mild changes in cerebral blood flow (64+/-5.8 cm/s supine, 58+/-4.9 cm/s upright, and 66+/-6.2 cm/s during ganglionic blockade; P:=0.07 by ANOVA). The slope of the regression between PaCO(2) and mean velocity was 1.6+/-0.18 cm/(s. mm Hg) supine, 1.3+/-0.14 cm/(s. mm Hg) during HUT, and 2.3+/-0.36 cm/(s. mm Hg) during ganglionic blockade (P:<0.05). Spontaneous PaCO(2) and ventilatory response to hypercapnia were also modulated by the level of sympathetic activity. Changes in sympathetic tone have a limited effect on cerebral blood flow at normal PaCO(2) levels. However, the sympathetic nervous system seems to attenuate the CO(2)-induced increase in cerebral blood flow. This phenomenon may indicate a moderate direct effect of the sympathetic nervous system on the cerebral vasculature. Furthermore, sympathetic activation tends to increase ventilation and thus can indirectly increase cerebrovascular tone.

Sympathetically mediated hypertension in autonomic failure.

BACKGROUND: Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. METHODS AND RESULTS: In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). CONCLUSIONS: Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.

Orthostatic intolerance: a disorder of young women.

Orthostatic intolerance (OI) is a cause of significant disability in otherwise healthy women seen by gynecologists. Orthostatic tachycardia is often the most obvious hemodynamic abnormality found in OI patients, but symptoms may include dizziness, visual changes, discomfort in the head or neck, poor concentration, fatigue, palpitations, tremulousness, anxiety, and, in some cases, fainting (syncope). It is the most common disorder of blood pressure regulation after essential hypertension, and patients with OI are traditionally women of childbearing age. Estimates suggest that at least 500,000 Americans suffer from some form of OI, and such patients comprise the largest group referred to centers specialized in autonomic disorders. This article reviews recent advances made in the understanding of this condition, potential pathophysiological mechanisms contributing to orthostatic intolerance, and therapeutic alternatives currently available for the management of these patients.

The pressor response to water drinking in humans : a sympathetic reflex?

BACKGROUND: Water drinking increases blood pressure profoundly in patients with autonomic failure and substantially in older control subjects. The mechanism that mediates this response is not known. METHODS AND RESULTS: We studied the effect of drinking tap water on seated blood pressure in 47 patients with severe autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure patients [PAF]). Eleven older controls and 8 young controls served as control group. We also studied the mechanisms that could increase blood pressure with water drinking. Systolic blood pressure increased profoundly with water drinking, reaching a maximum of 33+/-5 mm Hg in MSA and 37+/-7 in PAF mm Hg after 30 to 35 minutes. The pressor response was greater in patients with more retained sympathetic function and was almost completely abolished by trimethaphan infusion. Systolic blood pressure increased by 11+/-2.4 mm Hg in elderly but not in young controls. Plasma norepinephrine increased in both groups. Plasma renin activity, vasopressin, and blood volume did not change in any group. CONCLUSIONS: Water drinking significantly and rapidly raises sympathetic activity. Indeed, it raises plasma norepinephrine as much as such classic sympathetic stimuli as caffeine and nicotine. This effect profoundly increases blood pressure in autonomic failure patients, and this effect can be exploited to improve symptoms due to orthostatic hypotension. Water drinking also acutely raises blood pressure in older normal subjects. The pressor effect of oral water is an important yet unrecognized confounding factor in clinical studies of pressor agents and antihypertensive medications.

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Neurolab Autonomic Team.

Orthostatic intolerance is a common problem for inbound space travelers. There is usually tachycardia on standing but blood pressure may be normal, low or, rarely, elevated. This condition is analogous to the orthostatic intolerance that occurs on Earth in individuals with orthostatic tachycardia, palpitations, mitral valve prolapse, and light-headedness. Our studies during the Neurolab mission indicated that sympathetic nerve traffic is raised in microgravity and that plasma norepinephrine is higher than baseline supine levels but lower than baseline upright levels. A subgroup of patients with familial orthostatic intolerance differ from inbound space travelers in that they have an alanine-to-to-proline mutation at amino acid position 457 in their norepinephrine transporter gene. This leads to poor clearance of norepinephrine from synapses, with consequent raised heart rate. Clinical features of these syndromes are presented.

Interaction of genetic predisposition and environmental factors in the pathogenesis of idiopathic orthostatic intolerance.

BACKGROUND: The hemodynamic and autonomic abnormalities in idiopathic orthostatic intolerance (IOI) have been studied extensively. However, the mechanisms underlying these abnormalities are not understood. If genetic predisposition were important in the pathogenesis of IOI, monozygotic twins of patients with IOI should have similar hemodynamic and autonomic abnormalities. METHODS: We studied two patients with IOI and their identical twins. Both siblings in the first twin pair had orthostatic symptoms, significant orthostatic tachycardia, increased plasma norepinephrine levels with standing, and a greater than normal decrease in systolic blood pressure with trimethaphan infusion. RESULTS: Both siblings had a normal response of plasma renin activity to upright posture. In the second twin pair, only one sibling had symptoms of orthostatic intolerance, an orthostatic tachycardia, and raised plasma catecholamines with standing. The affected sibling had inappropriately low plasma renin activity with standing and was 8-fold more sensitive to the pressor effect of phenylephrine than the unaffected sibling. CONCLUSIONS: We conclude that in some patients, IOI seems to be strongly influenced by genetic factors. In others, however, IOI may be mainly caused by nongenetic factors. These findings suggest that IOI is heterogenous, and that both genetic and environmental factors contribute individually or collectively to create the IOI phenotype.

Effects of standing on cerebrovascular resistance in patients with idiopathic orthostatic intolerance.

PURPOSE: Patients with idiopathic orthostatic intolerance often have debilitating symptoms on standing that are suggestive of cerebral hypoperfusion despite the absence of orthostatic hypotension. SUBJECTS AND METHODS: We evaluated the effects of graded head-up tilt on cerebral blood flow as determined by transcranial Doppler measurements in 10 patients with idiopathic orthostatic intolerance (nine women, one man, 22 to 47 years) and nine age- and sex-matched control subjects. RESULTS: In patients, mean (+/- SD) arterial pressure at 0 degrees head-up tilt was 90 +/- 11 mm Hg and was well maintained at all tilt angles (90 +/- 11 mm Hg at 75 degrees). In controls, mean arterial pressure was 85 +/- 7 mm Hg at 0 degrees and 82 +/- 11 mm Hg at 75 degrees head-up tilt. There was a substantial decrease in peak velocity with increasing tilt angle in patients (28% +/- 10%) but not in controls (10% +/- 10% at 75 degrees, P <0.001). Similarly, mean velocity decreased 26% +/- 13% in patients and 12% +/- 11% in controls (P = 0.01). With increasing head-up tilt, patients had a significantly greater increase in regional cerebrovascular resistance than controls. CONCLUSIONS: In patients with idiopathic orthostatic intolerance, peak and mean middle cerebral artery blood flow velocity decreased in response to head-up tilt despite well sustained arterial blood pressure. These observations indicate that in this group of patients, regulation of cerebrovascular tone may be impaired and might therefore be a target for therapeutic interventions.

Acute effect of ephedrine on 24-h energy balance.

Ephedrine is used to help achieve weight control. Data on its true efficacy and mechanisms in altering energy balance in human subjects are limited. We aimed to determine the acute effect of ephedrine on 24-h energy expenditure, mechanical work and urinary catecholamines in a double-blind, randomized, placebo-controlled, two-period crossover study. Ten healthy volunteers were given ephedrine (50 mg) or placebo thrice daily during each of two 24-h periods (ephedrine and placebo) in a whole-room indirect calorimeter, which accurately measures minute-by-minute energy expenditure and mechanical work. Measurements were taken of 24-h energy expenditure, mechanical work, urinary catecholamines and binding of (+/-)ephedrine in vitro to human beta1-, beta2- and beta3-adrenoreceptors. Twenty-four-hour energy expenditure was 3.6% greater (8965+/-1301 versus 8648+/-1347 kJ, P<0.05) with ephedrine than with placebo, but mechanical work was not different between the ephedrine and placebo periods. Noradrenaline excretion was lower with ephedrine (0.032+/-0.011 microg/mg creatinine) compared with placebo (0.044+/-0.012 microg/mg creatinine) (P<0.05). (+/-)Ephedrine is a relatively weak partial agonist of human beta1- and beta2-adrenoreceptors, and had no detectable activity at human beta3-adrenoreceptors. Ephedrine (50 mg thrice daily) modestly increases energy expenditure in normal human subjects. A lack of binding of ephedrine to beta3-adrenoreceptors and the observed decrease in urinary noradrenaline during ephedrine treatment suggest that the thermogenic effect of ephedrine results from direct beta1-/beta2-adrenoreceptor agonism. An indirect beta3-adrenergic effect through the release of noradrenaline seems unlikely as urinary noradrenaline decreased significantly with ephedrine.

Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance.

BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of >/=30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses. METHODS AND RESULTS: Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55+/-5% versus 30+/-7%, P<0.02). After tyramine, NE spillover did not change significantly in patients but increased 50+/-10% in control subjects (P<0.001). The dose of isoproterenol required to increase heart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 microg, P<0.005), and the dose of phenylephrine required to increase systolic blood pressure 25 mm Hg was lower in patients than control subjects (105+/-11 versus 210+/-12 microg, P<0.001). Baroreflex sensitivity was lower in patients (12+/-1 versus 18+/-2 ms/mm Hg, P<0.02), but the intrinsic heart rate was similar in both groups. CONCLUSIONS: The decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.

Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure.

Supine hypertension, which is very common in patients with autonomic failure, limits the use of pressor agents and induces nighttime natriuresis. In 13 patients with severe orthostatic hypotension due to autonomic failure (7 women, 6 men, 72 +/- 3 yr) and supine hypertension, the effect of 30 mg nifedipine (n = 10) and 0.025 to 0.2 mg/h nitroglycerin patch (n = 11) on supine BP, renal sodium handling, and orthostatic tolerance was determined. Medications were given at 8 p.m.; patients stood up at 8 a.m. Nitroglycerin was removed at 6 a.m. Compared with placebo, nifedipine and nitroglycerin decreased systolic BP during the night by a maximum of 37 +/- 9 and 36 +/- 10 mmHg, respectively (P < 0.01). At 8 a.m., supine systolic BP was 23 +/- 7 mmHg lower with nifedipine than with placebo (P < 0.05), but was similar with nitroglycerin and placebo. Sodium excretion during the night was not reduced with nitroglycerin (0.13 +/- 0.02 mmol/mg creatinine [Cr] versus 0.15 +/- 0.03 mmol/mg Cr with placebo), but it was increased with nifedipine (0.35 +/- 0.06 mmol/mg Cr versus 0.13 +/- 0.02 mmol/mg Cr with placebo, P < 0.05). Nifedipine but not nitroglycerin worsened orthostatic hypotension in the morning. It is concluded that nifedipine and transdermal nitroglycerin are effective in controlling supine hypertension in patients with autonomic failure. However, nifedipine has a prolonged depressor effect and worsens orthostatic hypotension in the morning. The decrease in pressure natriuresis that would be expected with the substantial decrease in BP obtained with nitroglycerin and nifedipine may be offset by a direct effect of both drugs on renal sodium handling.

Orthostatic intolerance: emerging genetic and environmental etiologies.

Orthostatic intolerance (OI) is common after space flight and resembles the disabling idiopathic orthostatic intolerance commonly observed in otherwise healthy young individuals. OI can arise from reduced sympathetic nervous system activity and, paradoxically, also from increased sympathetic nervous system activity. Patients with early manifestations of pure autonomic failure demonstrate an etiology based upon reduced sympathetic nervous system activity. Patients with hyperadrenergia demonstrate an etiology based on increased sympathetic nervous activity. For many years, we have recognized that the microgravity environment induces adaptation in the cardiovascular system and its autonomic control mechanisms that lead to the presence of OI on return to gravity. Understanding the nature of OI in astronauts returning from space as well as in the relevant patient population on earth has been a priority of Vanderbilt's Center for Space Physiology and Medicine in recent years. A major purpose of the autonomic experiment in the Neurolab mission was to identify whether the OI experienced by astronauts on return to earth was best explained by a hypoadrenergic or hyperadrenergic state. To address this question, we analyzed sympathetic nervous system activity inflight by 1) measurement of plasma catecholamines; 2) assessment of peroneal microneurographic sympathetic nerve traffic; and 3) assessment of norepinephrine spillover and clearance during infusion of tritiated norepinephrine. These studies documented a slight (five bursts per minute) increase in muscle sympathetic nerve activity, a 200 pg/ml increase in plasma norepinephrine level, and a 350 ng/min increase in norepinephrine clearance. Plasma norepinephrine and norepinephrine spillover and clearance were also raised on recovery day. These data indicate that enhanced sympathetic activation, rather than reduced sympathetic activation, accompanies the orthostatic intolerance following microgravity.

Raised cerebrovascular resistance in idiopathic orthostatic intolerance: evidence for sympathetic vasoconstriction.

Patients with idiopathic orthostatic intolerance (IOI) exhibit symptoms suggestive of cerebral hypoperfusion and an excessive decrease in cerebral blood flow associated with standing despite sustained systemic blood pressure. In 9 patients (8 women and 1 man aged 22 to 48 years) with IOI, we tested the hypothesis that volume loading (2000 cc normal saline) and alpha-adrenoreceptor agonism improve systemic hemodynamics and cerebral perfusion and that the decrease in cerebral blood flow with head-up tilt (HUT) could be attenuated by alpha-adrenoreceptor blockade with phentolamine. At 5 minutes of HUT, volume loading (-20+/-3.2 bpm) and phenylephrine (-18+/-3.4 bpm) significantly reduced upright heart rate compared with placebo; the effect was diminished at the end of HUT. Phentolamine substantially increased upright heart rate at 5 minutes (20+/-3.7 bpm) and at the end of HUT (14+/-5 bpm). With placebo, mean cerebral blood flow velocity decreased by 33+/-6% at the end of HUT. This decrease in cerebral blood flow with HUT was attenuated by all 3 interventions. We conclude that in patients with IOI, HUT causes a substantial decrease in cerebrovascular blood flow velocity. The decrease in blood flow velocity with HUT can be attenuated with interventions that improve systemic hemodynamics and therefore decrease reflex sympathetic activation. Moreover, alpha-adrenoreceptor blockade also blunts the decrease in cerebral blood flow with HUT but at the price of deteriorated systemic hemodynamics. These observations may suggest that in patients with IOI, excessive sympathetic activity contributes to the paradoxical decrease in cerebral blood flow with upright posture.