(Hypertension. 1997;30:1062-1067.)
© 1997 American Heart Association, Inc.
Articles |
The Hypertension of Autonomic Failure and Its Treatment
From the Divisions of Clinical Pharmacology and Cardiology, the Clinical Research Center, and the Autonomic Dysfunction Center, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tenn.
Correspondence to Italo Biaggioni, MD, Clinical Research Center, AA-3228 MCN, Vanderbilt University, Nashville, TN 37232.
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Abstract |
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Abstract We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure
90 mm Hg. The prevalence
of hypertension was slightly greater in females (63%) than in males
(52%). Potential mechanisms responsible for this hypertension were
investigated. No correlation was found between blood volume and blood
pressure. Similarly, plasma norepinephrine (92±15 pg/mL)
and plasma renin activity (0.3±0.05 ng/mL per hour) were very low in
the subset of patients with pure autonomic failure and supine
hypertension (mean systolic/diastolic
pressure, 177±6/108±2 mm Hg, range 167/97 to 219/121). Supine
hypertension represents a challenge in the treatment of
orthostatic hypotension. We found these patients to be
particularly responsive to the hypotensive effects of transdermal
nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h
decreased systolic blood pressure by 36±7 mm Hg and may
effectively treat supine hypertension overnight, but the dose should be
individualized and used with caution.
Key Words: autonomic nervous system diseases • nitroglycerin • Shy-Drager syndrome • catecholamines
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Introduction |
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Primary autonomic failure is a severely disabling condition involving multiple-organ systems. It can occur with central nervous system involvement and extrapyramidal or cerebellar manifestations (multiple-system atrophy [MSA] or Shy-Drager syndrome), or it can involve only peripheral autonomic neurons (pure autonomic failure [PAF]).1 Common manifestations of primary autonomic failure are orthostatic hypotension, bladder and bowel dysfunction, and impotence. Perhaps the most disabling of these symptoms is orthostatic hypotension, and many patients are unable to stand for more than a few seconds without severe presyncope or syncope. Orthostatic hypotension in autonomic failure has been extensively studied and, although its treatment remains a challenge, several pharmacological and nonpharmacological measures are available.2 3
It seems paradoxical that many patients with primary autonomic failure also have supine hypertension. It often is undetected because blood pressure is commonly measured only in the seated position and, therefore, the actual prevalence of this complication is not known. Supine hypertension can be severe, and it complicates the treatment of orthostatic hypotension. In particular, drugs used for the treatment of orthostatic hypotension (eg, fludrocortisone and pressor agents) may worsen supine hypertension. The pathophysiologic mechanisms causing hypertension in patients with autonomic failure have not been defined. A better understanding of this process may provide key insights into the pathophysiology of essential hypertension.
To determine the prevalence and severity of supine hypertension in autonomic failure, we studied 117 patients characterized by severe primary autonomic failure. All other causes of orthostatic hypotension were excluded, and patients were placed on sodium balance in a metabolic ward. We also studied a subset of patients with PAF to address the potential contribution of sympathetic or renin mechanisms on supine hypertension. Finally, we examined potential treatment options for supine hypertension by evaluating the acute effects of several vasodilator agents.
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Methods |
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Study Population
We studied 117 consecutive patients with severe orthostatic hypotension due to primary autonomic failure over a 9-year period. All patients presenting to our referral center with this diagnosis were included in this study. Patients with secondary autonomic neuropathies (eg, diabetes mellitus or amyloidosis) were not included in this study. Patients were admitted to Vanderbilt's Clinical Research Center and were placed on a low-monoamine, caffeine-free diet containing 150 mEq/d sodium and 60 mEq/d potassium. Fludrocortisone and vasoactive medications were discontinued at least 1 week before assessment. Patients were in sodium balance for at least 3 days before study. This is a retrospective analysis of this patient data set.
Protocol
Orthostatic vital signs were determined by measuring
heart rate and brachial blood pressure with the blood pressure cuff
kept at heart level after 10 minutes supine and then after 3 minutes
standing or as long as tolerated. Autonomic failure was confirmed by a
battery of autonomic reflex tests.4 These tests included
determination of heart rate variability with controlled respiration and
determination of systolic blood pressure and heart rate
responses to hyperventilation, Valsalva's maneuver, isometric
handgrip, and immersion of one hand into ice water. Plasma
catecholamines were determined the morning after the
patient remained in the supine position overnight and again after 30
minutes in the upright position. Patients were instructed to stand as
much as possible during this period. If standing without symptoms was
not possible, they were permitted to walk or sit briefly until symptoms
abated. Blood samples were drawn from a heparin lock placed at least 30
minutes before the first blood draw.
Meal Challenge
The hypotensive effect of a standardized high-carbohydrate
breakfast (414 calories, 14 g of protein, 51.7 g of
carbohydrates, 16.8 g of fat) was evaluated. Patients were seated
in a chair with their feet on the floor. An automated brachial blood
pressure cuff (Dinamap, Critikon) was placed and blood pressure was
recorded every 5 minutes. Patients were fed the standardized
breakfast after 30 minutes of baseline recording. Seated blood
pressure was recorded every 5 minutes for the next 2.5 hours.
Baseline systolic blood pressure was determined by averaging
the five consecutive readings just before administration of the
breakfast. Trough systolic blood pressure was determined as the
lowest average of five consecutive readings after breakfast
administration.
Medication Trials
We measured the acute effects of hydralazine (50 mg PO),
minoxidil (2.5 mg PO), and placebo by monitoring blood pressure and
heart rate (Dinamap) in the supine position for 30 minutes before and
2.5 hours after drug administration. We also measured the effects of
transdermal nitroglycerine by placing a patch at 8:00
PM on the night of the test. The subjects remained supine
from 8:00 PM until 8:00 AM the next day. Blood
pressure and heart rate were measured manually at 1-hour intervals
throughout the night with care taken to avoid wakening the patient. The
patch was removed at 6:00 AM. The initial dose was 0.025
mg/h (Nitro-Dur patch) but was individualized in a given patient
by increasing the dose on subsequent nights until a hypotensive effect
was observed or a maximal dose of 0.1 mg/h was reached. The
effects of transdermal nitroglycerine were compared
with those of a placebo patch in a single-blind manner.
Analytical Methods
Plasma catecholamines were analyzed with a
high-pressure liquid chromatographic method as previously
described.5 Plasma renin enzymatic activity was assessed
by the conversion of angiotensinogen to
angiotensin I and is expressed as nanograms of
angiotensin I produced per liter of plasma per
hour.6 Red cell mass was measured with
51Cr-labeled erythrocytes. Plasma volume was measured with
131I-labeled albumin. Total blood volume was
calculated as red cell mass plus plasma volume.
Statistical Analysis
Results are presented as mean±SEM. Baseline
characteristics of subgroups were compared by unpaired two-tailed
t test. Intraindividual comparisons were tested by paired
two-tailed t test. Contingency-table analysis was
performed using Fisher's exact test. ANOVA was used for multiple
comparisons. Potential association between parameters was
assessed by linear regression analysis. The level of
significance was set at 
=0.05. Statistical analysis was
performed using Number Cruncher Statistical Software (NCSS) and Prism
program (GraphPad Software, Inc).
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Results |
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The clinical and biochemical characteristics of our patient population are shown in the Table
.
Fifty-four patients had isolated autonomic failure (pure autonomic
failure, PAF). Sixty-three patients had Parkinson's syndrome or other
central nervous system abnormalities in addition to autonomic failure
(MSA or Shy-Drager syndrome). No differences in supine or upright blood
pressure, heart rate, or plasma renin activity were observed between
PAF and MSA patients (Table). Both MSA and PAF patients had similar
changes in blood pressure and heart rate with standing. On average,
systolic blood pressure decreased 77±3 mm Hg on
standing, but heart rate increased only 10±1 bpm. This lack of an
adequate compensatory heart rate increase on standing is characteristic
of patients with severe autonomic failure.
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Patients with MSA had higher supine plasma norepinephrine
levels (1.20±0.08 nmol/L) compared with PAF (0.54±0.05
nmol/L) (Table
). This difference has been reported previously
and is thought to reflect relative sparing of peripheral
noradrenergic nerves in patients with
MSA.7 Plasma norepinephrine levels increased
when patients assumed the upright posture (to 1.67±0.13 and 0.84±0.09
nmol/L in MSA and PAF, respectively). By comparison, in
age-matched control subjects with a normal blood pressure response to
posture, plasma norepinephrine increased from 1.29±0.15 to
2.84±0.23 nmol/L. Although the postural increase in plasma
norepinephrine seen in autonomic failure patients was
statistically significant, it is inappropriately low compared with
normal control subjects, particularly considering the magnitude of
their orthostatic hypotension. Furthermore, it has been
shown that even this relatively small postural increase in plasma
norepinephrine in autonomic failure can be accounted for by
a reduction in norepinephrine clearance rather than an
actual increased in plasma appearance rate.8 Autonomic
failure patients (PAF and MSA) also had lower supine levels of plasma
renin activity compared with control subjects (0.4±0.1 in autonomic
failure patients versus 0.7±0.2 ng/mL per hour in control
subjects, P=.008 by unpaired t test) and an
impaired increase in plasma renin activity on standing, considering
their profound orthostatic hypotension. This blunted
response was particularly evident in PAF patients (upright plasma renin
activity 0.5±0.07 in PAF versus 1.0±0.3 ng/mL per hour in
controls, P=.02 by unpaired t test). This
impaired renin response has been reported previously.9
Fig 1 shows the distribution of supine
systolic and diastolic blood pressures in our
patient population. Supine hypertension, defined as a
diastolic blood pressure 90 mm Hg, was present
in 56% of patients. The prevalence of hypertension was similar in PAF
patients (54%) compared with MSA patients (47%), but it was slightly
greater in females than in males (63% and 52%, respectively,
P=.26, Fisher's exact test). No significant association was
found between age and blood pressure.
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Biochemical Characteristics
We studied a subset of patients with PAF that had a supine
diastolic blood pressure >95 mm Hg (n=25) to
determine the potential relationship between hypertension and plasma
norepinephrine or plasma renin activity. We compared these
patients with PAF patients without hypertension (n=29) and with normal
age-matched control subjects (n=18) (Fig 2). Postural increases in heart rate,
plasma norepinephrine, and renin were smaller in both
groups of patients compared with controls. The magnitude of
orthostatic hypotension was similar in patients with PAF
whether or not they had supine hypertension, which implies that the
severity of autonomic failure was similar between both groups of
patients. Hypertensive patients had similar supine plasma
norepinephrine and plasma renin levels as those without
hypertension. Supine plasma norepinephrine was 0.51±0.08
nmol/L, and plasma renin activity was 0.3±0.05 ng/mL per
hour in the hypertensive group, in whom mean supine blood pressure was
177±6/108±2 mm Hg (range 167/97 to 219/121) (Fig 2).
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Blood Volume and Hypertension
The relationship between total blood volume and supine blood
pressure was evaluated in 16 autonomic failure patients (PAF and MSA).
Red cell mass was low in these patients compared with predicted values
(20.0±1.6 and 24.6±0.8 mL/kg, respectively, P=.003 by
paired t test), which is in agreement with previous results
showing a high incidence of anemia in autonomic failure.10
Mean total blood volume, however, was not significantly different
(56.2±5.1 versus 57.1±4.3 mL/kg) because of a tendency toward higher
plasma volume in these patients (40.0±2.4 versus 36.6±1.4 mL/kg,
P=.07).
There was a wide variation in total blood volume (range 39.2 to 85.8 mL/kg), in red cell mass (from 11.8 to 29.2 mL/kg), and in plasma volume (from 27.4 to 59.8 mL/kg), but no correlation was found between any of these parameters and either supine systolic (range 135 to 228 mm Hg, r<.1) or diastolic (range 97 to 121 mm Hg, r<.1) blood pressure.
Medication Trials
Supine blood pressure changes in response to meal and test
medications are presented in Fig 3. PAF patients had a profound
hypotensive response to a standardized breakfast (-44±2 mm Hg,
n=16). Among the vasodilators tested, patients were particularly
responsive to transdermal nitroglycerin, which
decreased systolic blood pressure by 36±7 mm Hg (n=7).
The dose of nitroglycerin required to produce this
effect varied among individuals and ranged from 0.025 to 0.1
mg/h. By comparison, 50 mg of hydralazine decreased
systolic blood pressure by 13±7 mm Hg (n=7), and 2.5 mg
of minoxidil decreased systolic blood pressure by 22±8
mm Hg (n=5). We studied the time course of the hypotensive effect of
transdermal nitroglycerine in 10 additional subjects
(Fig 4). The decrease in blood pressure
produced by nitroglycerine compared with placebo was
significant at 4 hours after application, and this effect was sustained
throughout the testing period.
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SBP)
is presented on the y axis.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We found a high incidence of hypertension in a group of 117 patients with severe disabling autonomic failure. Fifty-six percent of these patients had supine diastolic blood pressure
90 mm Hg. Supine diastolic blood pressure was
95 mm Hg in 43% of patients, and supine blood pressures as
high as 228/140 mm Hg were observed in our patients. The
association between supine hypertension and autonomic failure has been
recognized previously, but the magnitude of this problem has not been
characterized previously in a large patient population uniformly
characterized by primary severe autonomic failure. The results of this
study indicate that supine hypertension is a common occurrence in
autonomic failure and frequently can be severe. The mechanisms responsible for supine hypertension in patients with autonomic failure are not known. It could be proposed that hypertension is somehow the result of the underlying neurological processes responsible for autonomic failure. It is unlikely, however, that autonomic failure itself is responsible for supine hypertension, because chronic experimental sympathetic blockade produces sustained hypotension rather than hypertension.11 Patients with autonomic failure have severely impaired baroreflex function, and patients with isolated baroreflex failure are characterized by severe paroxysmal hypertension.12 The hypertension of baroreflex failure, however, is due to increased sympathetic nervous system activity13 14 and, therefore, cannot explain the hypertension of autonomic failure. In addition to autonomic failure, patients with MSA suffer from degeneration of basal ganglia similar to that seen in Parkinson's disease. Hypertension is common in this age group, and it has been reported previously that blood pressure in patients with Parkinson's disease is not different from controls.15 This conclusion, however, was based on casual blood pressure readings and the use of historical controls. A case-control study found that Parkinson's patients had a lower blood pressure and a lower incidence of hypertension compared with age-matched controls.16 Furthermore, this tendency toward a lower blood pressure correlated with the severity of rigidity, but not with the severity of tremor; it is noteworthy that rigidity is the dominant feature of MSA, whereas tremor is mild, if present at all.
It is remarkable, therefore, that autonomic failure patients would suffer from hypertension, considering that their neurological abnormalities tend to reduce blood pressure. We speculate that there is an underlying mechanism(s) independent of the cause of autonomic failure that is responsible for hypertension in about half of our patients. Because autonomic failure patients lack the buffering capacity normally provided by baroreflex function, the mechanisms responsible for hypertension are likely magnified in these patients. Assuming that similar processes are present in other forms of hypertension, then elucidating the mechanisms responsible for hypertension in autonomic failure may provide important clues as to the underlying pathophysiology of essential hypertension.
Supine hypertension in autonomic failure could be explained by an increase in intravascular volume, an increase in cardiac output, an increase in vascular tone, or a combination of these mechanisms. It has been reported previously that patients with autonomic failure have a normal plasma volume.17 Similarly, in this study mean blood volume was no different than predicted values in this group of autonomic failure patients evaluated on sodium balance in a metabolic ward. Furthermore, no correlation was found between blood volume and blood pressure, even though a wide range of blood volume values was observed in this study group. It is unlikely, therefore, that an increase in blood volume is the main mechanism responsible for supine hypertension in autonomic failure. This is not to say that these patients are not sensitive to changes in intravascular volume. It has been shown that relatively small adjustments in plasma volume produced by altering dietary sodium can result in substantial changes in blood pressure in autonomic failure patients.17
If supine hypertension in autonomic failure cannot be explained by increased plasma volume, then it must be due either to increased cardiac output or to increased vascular resistance. Several investigators have shown consistently that cardiac output is not increased in patients with autonomic failure compared with normal control subjects.18 19 In a previous study, we found that autonomic failure patients with supine hypertension had a cardiac output similar to normotensive controls and, therefore, their hypertension was due to an increase in vascular resistance.20 Our studies so far have not been able to establish the mechanisms responsible for this increased vascular resistance, but some of our findings are worth noting. For example, both plasma norepinephrine levels and plasma renin activity were very low in patients with PAF and supine hypertension. Plasma norepinephrine is not always a reliable indicator of sympathetic activity in autonomic failure. Norepinephrine kinetic studies have shown that upright posture will elevate plasma norepinephrine in these patients because of a reduction in norepinephrine clearance rather than an actual increase in norepinephrine spillover. Nonetheless, supine norepinephrine spillover, estimated by this technique, is low in autonomic failure.8 It is unlikely, therefore, that sympathetic or renin mechanisms play a substantial role in their hypertension. The hypersensitivity of these patients to transdermal nitroglycerine suggests that at least the pathways distal to nitric oxide production are intact, because nitroglycerine acts as a nitric oxide donor. On the other hand, reduced nitric oxide production remains a possibility that requires further study. It is of interest that an increase in myocardial contractility has also been reported in these patients,20 raising the possibility that a common mechanism may be responsible for the increased vascular smooth muscle tone and myocardial contractility. The potential contribution of vasoconstrictor hormones, such as vasopressin or endothelin, or myogenic arteriolar vasoconstriction also needs to be addressed in future studies.
The presence of supine hypertension complicates treatment of orthostatic hypotension in autonomic failure patients. Orthostatic hypotension is usually treated with pressor agents and the mineralocorticoid fludrocortisone, but these agents also aggravate supine hypertension. One approach for treating orthostatic hypotension in patients with supine hypertension is to use only short-acting pressor agents.21 Their use is best restricted to a dose in the early morning and early afternoon when orthostatic symptoms are at their worst. This schedule allows 2 to 3 hours of upright activity after each dose. Patients must be instructed to avoid lying down after medication and to rest in a seated rather than supine position if they grow tired during the day. Symptoms of orthostatic hypotension tend to lessen during the evening, and we recommend avoiding pressor agents at that time of day. These simple procedures are usually enough to avoid worsening supine hypertension during the day. However, most patients require the addition of fludrocortisone to treat orthostatic hypotension effectively, which will aggravate supine hypertension.22
In many cases, therefore, worsening of supine hypertension is the price to pay for treating disabling orthostatic hypotension. Unresolved issues are how much harm results from supine hypertension and whether hypertension should be treated in these patients. The aim of treating essential hypertension is to prevent end-organ damage such as stroke, nephropathy, and cardiomyopathy. The natural history of hypertension in autonomic failure, however, is not known and may be different from that of essential hypertension. There are indeed several differences between essential hypertension and the hypertension of autonomic failure. End-organ damage appears to correlate with plasma renin activity in essential hypertension.23 24 It could be speculated, therefore, that the low renin present in autonomic failure provides protection against hypertensive complications. Also, end-organ damage occurs only after long-standing, untreated essential hypertension. The prognosis of autonomic failure, on the other hand, depends on the underlying condition. Patients with MSA have a median survival of less than 10 years from the onset of symptoms25 and, therefore, progression of their underlying disease rather than complications of hypertension will dominate their clinical picture. On the other hand, it is believed that patients with PAF have a better prognosis, and some may have a normal life expectancy. Even these patients will have intermittent rather than sustained hypertension, because blood pressure will be elevated only while supine and mostly at night. Whether treatment of supine hypertension will improve prognosis in autonomic failure, therefore, is not known. It will be difficult to obtain a definite answer to this question because prolonged follow-up would be required in a substantial number of patients with this relatively rare disorder.
A second reason to treat supine hypertension in patients with autonomic failure is to avoid the negative effects of hypertension on blood volume. It has been proposed that supine hypertension leads to pressure diuresis in the supine position, relative volume depletion during the night, and worsening of orthostatic hypotension upon rising. Nocturnal volume depletion could explain the clinical observation that these patients tend to be more symptomatic from orthostatic hypotension early in the morning and improve during the day. Furthermore, it has been shown that sleeping in the head-up tilt position decreases nocturnal diuresis,26 and we encourage patients to sleep with the head of the bed elevated 6 to 10 inches to benefit from this phenomenon.
A similar result theoretically could be obtained with a "pharmacological tilt," by reducing blood pressure with antihypertensive agents. This would provide an alternative rationale to treat supine hypertension during the night. Our studies indicate that supine hypertension can be treated effectively with vasodilators. We did not find hydralazine or minoxidil to be as effective as transdermal nitroglycerine in lowering blood pressure. Preliminary uncontrolled observations suggest that calcium-channel blockers are also effective hypotensive agents in these patients. Ingestion of food is also known to induce dramatic, although transient, reductions in blood pressure in patients with autonomic failure.27 A bedtime snack may be useful in some patients, but its effect is not sustained.
Transdermal nitroglycerine has practical advantages over other potential treatments for supine hypertension. This sustained release preparation provides a hypotensive effect throughout the night, and its actions can be terminated by removal of the patch in the event of exaggerated hypotension. This drug was effective at very low doses, ranging from 0.025 to 0.1 mg/h. Doses need to be individualized because patients can be extremely sensitive to its effect; profound hypotension can result. For this reason, we chose a preparation (Nitro-Dur patch) that is formulated into a matrix rather than a pouch, so that it could be divided to titrate the dose without loss of active medication. Patients are instructed to remove the patch before rising in the morning and to take great care if they need to assume the upright posture during the night, because their orthostatic hypotension may be exacerbated. We have not observed this complication, but the potential risk of falling must be weighed against the potential benefit of reducing supine blood pressure. We find nitroglycerine to be effective in treating supine hypertension, but more studies are needed to determine whether this treatment will reduce nocturnal diuresis and improve daytime orthostatic hypotension.
In summary, supine hypertension can be found in up to 50% of patients with severe autonomic failure. Previous studies have shown that this hypertension is characterized by increased systemic vascular resistance. The mechanisms increasing vascular resistance in the face of low plasma norepinephrine and plasma renin activity are not known. Elucidation of these mechanisms may provide insight into the underlying pathophysiology of essential hypertension. Transdermal nitroglycerine is effective in reducing supine blood pressure in patients with autonomic failure. It is not known, however, whether treatment of supine hypertension will improve prognosis in patients with autonomic failure.
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Acknowledgments |
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This work was supported by grant R00095 from the National Institutes of Health and by NASA NAGW 3854 and NAS9-19483. Dr Jordan was supported by the Deutsche Forschungsgemeinschaft. We thank Dorothea Boemer for editorial assistance, Dr David Robertson for useful suggestions on the design of these studies, and Bonnie Black, Sylvia Dickinson, Riche Norman, and the nurses of Vanderbilt's Clinical Research Center for their assistance in the care and study of these patients. We also acknowledge the many physicians that referred patients to us and the generosity of the patients for agreeing to participate in this study.
Received April 28, 1997; first decision May 29, 1997; accepted May 29, 1997.
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 W Singer, T L Opfer-Gehrking, B R McPhee, M J Hilz, A E Bharucha, and P A Low Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension J. Neurol. Neurosurg. Psychiatry, September 1, 2003; 74(9): 1294 - 1298. [Abstract] [Full Text] [PDF]
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 A. Diedrich, J. Jordan, J. R. Shannon, D. Robertson, and I. Biaggioni Modulation of QT Interval During Autonomic Nervous System Blockade in Humans Circulation, October 22, 2002; 106(17): 2238 - 2243. [Abstract] [Full Text] [PDF]
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J Gutierrez, R Santiesteban, H Garcia, A Voustianiouk, R Freeman, and H Kaufmann High blood pressure and decreased heart rate variability in the Cuban epidemic neuropathy J. Neurol. Neurosurg. Psychiatry, July 1, 2002; 73(1): 71 - 72. [Abstract] [Full Text] [PDF]
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 R. Vallejo, G. DeSouza, and J. Lee Shy-Drager Syndrome and Severe Unexplained Intraoperative Hypotension Responsive to Vasopressin Anesth. Analg., July 1, 2002; 95(1): 50 - 52. [Abstract] [Full Text] [PDF]
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 M. Ino, T. Yoshinaga, M. Wakamori, N. Miyamoto, E. Takahashi, J. Sonoda, T. Kagaya, T. Oki, T. Nagasu, Y. Nishizawa, et al. Functional disorders of the sympathetic nervous system in mice lacking the alpha 1B subunit (Cav 2.2) of N-type calcium channels PNAS, April 5, 2001; (2001) 81089398. [Abstract] [Full Text]
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 O. Oldenburg, A. Mitchell, J. Nurnberger, S. Koeppen, R. Erbel, T. Philipp, and A. Kribben Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension J. Am. Coll. Cardiol., January 1, 2001; 37(1): 219 - 223. [Abstract] [Full Text] [PDF]
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J. R. Shannon, J. Jordan, A. Diedrich, B. Pohar, B. K. Black, D. Robertson, and I. Biaggioni Sympathetically Mediated Hypertension in Autonomic Failure Circulation, June 13, 2000; 101(23): 2710 - 2715. [Abstract] [Full Text] [PDF]
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M. J. Carvalho, A. H. van den Meiracker, F. Boomsma, M. Lima, J. Freitas, A. J. M. i.’t Veld, and A. Falcao de Freitas Diurnal Blood Pressure Variation in Progressive Autonomic Failure Hypertension, April 1, 2000; 35(4): 892 - 897. [Abstract] [Full Text] [PDF]
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 J. JORDAN, J. R. SHANNON, B. POHAR, S. Y. PARANJAPE, D. ROBERTSON, R.-M. ROBERTSON, and I. BIAGGIONI Contrasting Effects of Vasodilators on Blood Pressure and Sodium Balance in the Hypertension of Autonomic Failure J. Am. Soc. Nephrol., January 1, 1999; 10(1): 35 - 42. [Abstract] [Full Text]
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J. R. Shannon, J. Jordan, B. K. Black, F. Costa, and D. Robertson Uncoupling of the Baroreflex by NN-Cholinergic Blockade in Dissecting the Components of Cardiovascular Regulation Hypertension, July 1, 1998; 32(1): 101 - 107. [Abstract] [Full Text] [PDF]
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J. Jordan, J. R. Shannon, B. K. Black, R. H. Lance, M. D. Squillante, F. Costa, and D. Robertson NN-Nicotinic Blockade as an Acute Human Model of Autonomic Failure Hypertension, May 1, 1998; 31(5): 1178 - 1184. [Abstract] [Full Text] [PDF]
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M. Ino, T. Yoshinaga, M. Wakamori, N. Miyamoto, E. Takahashi, J. Sonoda, T. Kagaya, T. Oki, T. Nagasu, Y. Nishizawa, et al. Functional disorders of the sympathetic nervous system in mice lacking the alpha 1B subunit (Cav 2.2) of N-type calcium channels PNAS, April 24, 2001; 98(9): 5323 - 5328. [Abstract] [Full Text] [PDF]
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