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(Circulation. 2000;102:2611.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Severely Impaired Baroreflex-Buffering in Patients With Monogenic Hypertension and Neurovascular Contact

Jens Jordan, MD; Hakan R. Toka, MD; Karsten Heusser, MD; Okan Toka, MD; John R. Shannon, MD; Jens Tank, MD; Andre Diedrich, MD; Christine Stabroth, MD; Mandy Stoffels, RN; Ramin Naraghi, MD; Wolfgang Oelkers, MD; Herbert Schuster, MD; Hans P. Schobel, MD; Hermann Haller, MD; Friedrich C. Luft, MD

From the Clinical Research Center, Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt-University, and the Department of Endocrinology, Klinikum Benjamin Franklin, Free University, Berlin, and the Department of Internal Medicine and Nephrology and Department of Neurosurgery, Friedrich-Alexander University, Erlangen, Germany; and the Autonomic Dysfunction Service, Vanderbilt University, Nashville, Tenn.

Correspondence to Jens Jordan, MD, Clinical Research Center, Franz-Volhard-Clinic, Humboldt University, Wiltbergstraße 50, 13125 Berlin, Germany. E-mail jordan{at}fvk-berlin.de

	Abstract

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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 µg in patients and 135±35 µg in control subjects before ganglionic blockade and 5.4±0.4 µg in patients and 13±4.8 µg 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.

Key Words: baroreceptors • genetics • hypertension • nervous system, autonomic • receptors

	Introduction

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Bilginturan et al¹ first described autosomal dominant hypertension and brachydactyly. The gene responsible for the syndrome was mapped to chromosome 12p² . Affected individuals exhibit a profoundly accelerated increase in blood pressure with age.³ We showed earlier that affected individuals are not salt sensitive and that plasma renin activity and aldosterone respond normally to volume expansion and depletion.³ We subsequently showed by MR tomography that all 15 affected family members tested had a left-sided loop of the posterior inferior cerebellar artery (PICA) impinging on the rostroventrolateral medulla, compared with none of 11 nonaffected family members.⁴ Pulsatile compression of the rostroventrolateral medulla may contribute to essential hypertension.^{5 6} This hypothesis is supported by the observation that neurosurgical decompression of the brain stem improves blood pressure control.⁷ Animal studies suggest that pulsatile compression of the rostroventrolateral medulla increases blood pressure through sympathetic activation.⁸ Whether similar autonomic abnormalities occur in humans is not known. We tested the hypothesis that in patients with monogenic hypertension, brachydactyly, and neurovascular contact, the hypertension is mediated through sympathetic activation. Furthermore, we tested whether these changes were caused by increased sympathetic nerve traffic, increased vascular sensitivity, or impaired baroreflex buffering.

	Methods

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Subjects
Five younger family members with hypertension and brachydactyly traveled to Germany to participate in this study (3 men, 2 women, 26±3.4 years old, 57±4.0 kg, 152±2.4 cm tall). Their results were compared with those of healthy normotensive control subjects of similar age. Written informed consent was obtained. All studies were approved by the institutional review board.

Protocol
Three days before the study, volunteers received a 150-mmol sodium diet free of substances that could interfere with catecholamine measurements. All vasoactive medications were discontinued 5 half-lives before testing. The patients underwent a physical examination, MRI imaging of the brain stem,⁴ and a series of autonomic tests on separate days.

Posture Study
After the patients had remained overnight in the supine position, venous samples for plasma renin activity and aldosterone concentrations were obtained from a heparin lock placed 30 minutes before the first blood draw. Blood samples were again obtained after 30 minutes in the standing position. Automated measurements of blood pressure and heart rate were made (Dinamap, Criticon). On a separate day, the study was repeated after an intravenous infusion of 1000 mL normal saline in 30 minutes.

Autonomic Reflex Testing
Sinus arrhythmia was assessed during controlled breathing (5-second inhalation and 5-second exhalation for 90 seconds). The sinus arrhythmia ratio was calculated as the ratio of the longest to the shortest RR interval during these 90 seconds. Patients performed a Valsalva maneuver (40 mm Hg pressure for 15 seconds). Blood pressure and heart rate responses to isometric handgrip (30% maximum contraction for 1 minute) and cold pressor testing were also determined.⁹

Pharmacological testing was conducted with the subject recumbent 2.5 hours after the last meal. Heart rate was determined with a continuous ECG, blood pressure by an indwelling catheter in the radial artery, and changes in stroke volume by impedance cardiography.¹⁰ Leg blood flow was determined before and during complete ganglionic blockade by occlusion plethysmography (EC 5R, Hokanson). Responses to incremental intravenous bolus doses of nitroprusside and phenylephrine were evaluated before ganglionic blockade. Thereafter, we infused the ganglionic blocker trimethaphan (Cambridge Pharmaceuticals) starting at 1 mg/min and increasing at 6-minute intervals until the efferent arc of the baroreflex was completely blocked.¹¹ Bolus doses of phenylephrine were then administered just as before blockade.

The baroreflex slope was determined at the linear portion of the sigmoidal relation between phenylephrine-induced blood pressure changes and changes in RR interval. The spontaneous baroreflex slope was determined by the sequence technique.¹² The doses of each drug that would change blood pressure by 12.5 mm Hg were determined by extrapolation from individual dose-response curves.

Microneurography
During the microneurography study, heart rate was determined by continuous ECG and beat-by-beat blood pressure by photoplethysmography (Finapres, Ohmeda). Microneurography recordings were obtained as described previously.¹³

Analytical Methods
Plasma and urinary catecholamines were determined by a modification of a high-performance liquid chromatographic method.¹⁴ Plasma vasopressin concentration was determined by a radioimmunoassay.

Statistics
All data are expressed as mean±SEM. Intraindividual and interindividual differences were compared by paired and unpaired t tests, respectively. ANOVA testing for repeated measures was used for multiple comparisons. If necessary, data were logarithmically transformed before analysis. Relationships between parameters were assessed by linear regression analysis. A value of P<0.05 was considered significant.

	Results

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Clinical Characteristics
All 5 patients had severe arterial hypertension. None had cardiovascular complications. All had a normal creatinine clearance, and none had microalbuminuria. Echocardiography showed normal systolic function. One patient had mild left ventricular hypertrophy. However, none had signs of impaired left ventricular filling. MRI of the brain stem showed a left-sided loop of the PICA in all affected subjects (Figure 1).⁴

View larger version (126K): [in this window] [in a new window]   Figure 1. T2-weighted high-resolution MR tomography (MRT) of medulla oblongata in a nonaffected subject (A, B) and a patient with brachydactyly and hypertension (C, D). A, In nonaffected subject, axial scan does not show signs of neurovascular contact (NVC). There is no vascular attachment to surface of ventrolateral medulla (VLM) and root entry zone of cerebral nerves 9 and 10. B, Similarly, there was no evidence of vascular compression of VLM in coronal plane. C, In a patient with brachydactyly and hypertension, axial T2-weighted MRT showed a loop of PICA on left side impinging on VLM and root entry zone of cerebral nerves 9 and 10. D, Coronal view shows course of loop in front of VLM causing NVC at left. VA indicates vertebral artery.

Posture Studies and Catecholamines
Figure 2 illustrates supine and upright blood pressure and heart rate. Without volume loading, blood pressure was 135±6.7/81±4.6 mm Hg and increased to 148±3.2/99±5.7 mm Hg after 5 minutes in the standing position (P=0.1 for systolic blood pressure and P=0.01 for diastolic blood pressure). This increase in blood pressure was associated with a change in heart rate from 59±3.2 bpm supine to 87±5.5 bpm upright. Before volume loading, supine blood pressure was 140±6.0/84±6.0 mm Hg and supine heart rate was 63±4 bpm. Immediately after volume loading, supine blood pressure was 140±5.8/84±4.0 mm Hg and supine heart rate was 66±5.0 bpm. With volume loading, the increase in blood pressure with standing was attenuated. After 5 minutes of standing, blood pressure was 141±3.9/94±4.4 mm Hg and heart rate was 71±4.2 bpm. Plasma norepinephrine and epinephrine concentrations were not excessively increased in the supine or upright position (Table). Urinary excretion of norepinephrine was 112±24 nmol/d (normal range 136 to 621 nmol/d). Urinary epinephrine excretion was 38±8.2 nmol/d (normal range 22 to 109 nmol/d).

View larger version (23K): [in this window] [in a new window]   Figure 2. Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) with standing. Patients stood up at 0 minutes. Without volume administration (top), blood pressure and heart rate increased substantially with standing. Intravenous infusion of 1000 mL normal saline attenuated blood pressure and heart rate increase with standing (bottom).

View this table: [in this window] [in a new window]   Table 1. Plasma Catecholamines

Autonomic Reflex Testing
Respiratory sinus arrhythmia was 1.3±0.055. During Valsalva maneuver phase II, blood pressure increased 12±11/26±9.8 mm Hg. Blood pressure increased 45±12/24±6.3 mm Hg during phase IV. The Valsalva heart rate ratio was 1.4±0.19. With hand-grip testing, blood pressure increased 36±5.0/24±2.7 mm Hg. After 1 minute of cold pressor testing, blood pressure increased 46±8.8/27±5.5 mm Hg. In 4 patients, blood pressure increased profoundly with cold pressor testing (range 45 to 66/22 to 41 mm Hg); 1 patient had a clearly abnormal response (9/7 mm Hg change) but had no pain during the test. The pressor responses to hand-grip exercise and to cold were exaggerated compared with control subjects.¹⁵

Responses to Complete Ganglionic Blockade
Before trimethaphan infusion, blood pressure was 150±4.9/86±1.8 mm Hg and heart rate was 67±6.3 bpm. Figure 3 illustrates changes in blood pressure, heart rate, and stroke volume with increasing trimethaphan infusion. When complete ganglionic blockade was achieved, blood pressure and heart rate were 134±4.9/82±4.1 mm Hg and 90±2.6 bpm, respectively. In control subjects,¹⁵ blood pressure in the supine position was 129±4.0/65±3.0 mm Hg before trimethaphan. With complete ganglionic blockade, blood pressure decreased to 90±6/49±2.4 mm Hg (P<0.01 compared with patients). Decreases in both systolic (P<0.05) and diastolic blood pressure (P<0.01) were smaller in patients than in control subjects. In patients, the decrease in blood pressure was associated with a 7.5±5.3% decrease in cardiac output. Stroke volume decreased 31±5.0%. Leg blood flow increased from 5.9±0.6 mL·100 mL^-1·s^-1 at baseline to 11±2 mL·100 mL^-1·s^-1 during complete ganglionic blockade. Plasma norepinephrine concentration decreased profoundly during ganglionic blockade (Table). In patients, plasma vasopressin concentration was 0.47±0.02 pg/mL at baseline and 0.84±0.13 pg/mL during complete ganglionic blockade (Figure 4). In control subjects, in contrast, plasma vasopressin concentration increased profoundly during ganglionic blockade (1.6±0.17 pg/mL at baseline, 39±13 pg/mL during ganglionic blockade).

View larger version (14K): [in this window] [in a new window]   Figure 3. Top, Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) with incremental infusion of trimethaphan. Blood pressure decreased substantially with trimethaphan. Bottom, Changes in stroke volume with incremental infusion of trimethaphan.

View larger version (10K): [in this window] [in a new window]   Figure 4. Plasma vasopressin concentrations at baseline and during ganglionic blockade with trimethaphan in patients and in young control subjects. In control subjects, ganglionic blockade is associated with a profound baroreflex-mediated increase in plasma vasopressin concentration. A similar increase was observed in a previous study by Baylis and Robinson.32 In patients, plasma vasopressin concentration increased slightly or not at all during ganglionic blockade.

Sensitivity to Phenylephrine and Nitroprusside and Baroreflex Slope
Before ganglionic blockade, patients were extremely hypersensitive to the pressor effect of phenylephrine (Figure 5). The phenylephrine dose that increased systolic blood pressure 12.5 mm Hg was 8.0±2.0 µg in patients and 135±35 µg in control subjects (Figure 6). During ganglionic blockade, the phenylephrine dose that increased systolic blood pressure 12.5 mm Hg was 5.4±0.4 µg in patients and 13±4.8 µg in control subjects (P<0.0001 between groups, P<0.001 between interventions, P<0.01 for the interaction between group and intervention). Ganglionic blockade potentiated the pressor effect by factors of 1.5±0.5 and 15±4.3 in patients and control subjects, respectively (P<0.01). Without ganglionic blockade, patients were hypersensitive to the depressor effect of nitroprusside (Figure 7). The nitroprusside dose that decreased systolic blood pressure 12.5 mm Hg without ganglionic blockade was 0.20±0.066 µg/kg in patients and 1.8±0.50 in control subjects (P<0.01) (Figure 8). The baroreflex slope determined by phenylephrine bolus application was 9.4±1.6 ms/mm Hg. Baroreflex slope determined by the sequence technique was 12±2.0 ms/mm Hg. In 3 patients, baroreflex slope was above the 90th percentile for age, and in 2 patients, it was between the 90th and 95th percentiles.¹²

View larger version (18K): [in this window] [in a new window]   Figure 5. Changes in systolic blood pressure with incremental bolus doses of phenylephrine before (top) and during (bottom) ganglionic blockade in patients with monogenic brachydactyly and hypertension (HTN) and in young normotensive control subjects. Before ganglionic blockade, patients were extremely hypersensitive to pressor effect of phenylephrine. During ganglionic blockade, sensitivity to phenylephrine was not significantly different between patients and control subjects.

View larger version (16K): [in this window] [in a new window]   Figure 6. Doses of phenylephrine that increased systolic blood pressure 12.5 mm Hg before and during ganglionic blockade with trimethaphan in patients with monogenic brachydactyly and hypertension (HTN) and in young normotensive control subjects. In control subjects, sensitivity to pressor effect of phenylephrine increased 15-fold after interruption of baroreflex with trimethaphan. Patients were extremely hypersensitive to pressor effect of phenylephrine before ganglionic blockade; with ganglionic blockade, sensitivity to phenylephrine increased only 1.5-fold.

View larger version (15K): [in this window] [in a new window]   Figure 7. Changes in systolic blood pressure with incremental bolus doses of nitroprusside before ganglionic blockade with trimethaphan in patients with monogenic brachydactyly and hypertension (HTN) and in young normotensive control subjects. Patients were hypersensitive to depressor effect of nitroprusside.

View larger version (16K): [in this window] [in a new window]   Figure 8. Doses of nitroprusside that decreased systolic blood pressure 12.5 mm Hg before ganglionic blockade. Patients were 9-fold more hypersensitive to depressor effect than control subjects.

Microneurography
Representative microneurography recordings are illustrated in Figure 9. Baseline sympathetic activity in the supine position was 15±4.6 bursts/min. In a previous study, resting muscle sympathetic nerve activity was 12±6 bursts/min in young normotensive control subjects and 14±9 bursts/min in young borderline hypertensives.¹³ Microneurography incidence was 22±6.5 bursts/100 heartbeats. With cold pressor testing, muscle sympathetic nerve activity increased 7.5±6.8 bursts/min (11±10 bursts/100 heartbeats). By comparison, cold pressor testing elicited an increase in muscle sympathetic nerve activity by 14±10 bursts/min in normotensive control subjects and by 11±8.0 bursts/min in patients with borderline hypertension.¹³ With lower-body negative pressure, muscle sympathetic nerve activity increased from 19±5.8 bursts/min (31±8.6 bursts/100 heartbeats) at 0 mm Hg to 24±6.5 bursts/min (36±9.0 bursts/100 heartbeats) at -10 mm Hg suction (n=4). This increase in sympathetic nerve traffic during lower-body negative pressure was associated with a decrease in forearm blood flow from 8.7±1.4 mL/100 mL to 6.6±0.8 mL/100 mL. Blood pressure was 131±4.6/74±2.6 mm Hg at 0 mm Hg and 134±3.3/76±2.0 mm Hg at -10 mm Hg lower-body negative pressure.

View larger version (16K): [in this window] [in a new window]   Figure 9. Spontaneous muscle sympathetic nerve activity in 2 patients with monogenic brachydactyly and hypertension (top) and in a normotensive and a hypertensive control subject of similar age (bottom). Muscle sympathetic nerve activity was not increased in patients.

	Discussion

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Our main finding was that in patients with monogenic hypertension, brachydactyly, and neurovascular contact, blood pressure during complete ganglionic blockade was 44 mm Hg greater than in control subjects. However, sympathetic stimuli caused an excessive increase in blood pressure. This increase was not due to increased sympathetic nerve traffic. The patients were extremely hypersensitive to phenylephrine and nitroprusside. With ganglionic blockade, the pressor effect of phenylephrine was only slightly augmented in patients but increased dramatically in control subjects. Furthermore, with ganglionic blockade, plasma vasopressin concentration increased profoundly in control subjects but changed little in patients.

We used trimethaphan to determine the contribution of autonomic nervous system activity to blood pressure control.¹⁶ Ganglionic blockade at the level achieved in this study abolishes sympathetic and parasympathetic modulation of heart rate and blood pressure.¹⁵ Even with substantial changes in blood pressure, heart rate does not change and muscle sympathetic nerve activity is abolished.¹¹ The blockade is associated with decreased plasma norepinephrine concentrations as low as seen in patients with severe pure autonomic failure.¹⁵ Plasma catecholamines and muscle sympathetic nerve activity were low normal in our patients, suggesting that the sympathetic contribution to supine blood pressure was not increased. In this regard, our patients resemble patients with secondary hypertension rather than patients with essential hypertension.¹⁷ Because sympathetic nerve traffic is not evenly distributed throughout the body,¹⁸ muscle sympathetic nerve activity may not necessarily reflect overall sympathetic tone. Yet, blood pressure decreased with complete ganglionic blockade to a lesser degree than in control subjects,^{15 19} which further supports there being no increase in basal sympathetic tone. Blood pressure during ganglionic blockade was still greater in patients than in control subjects. Thus, the increase in basal blood pressure is not entirely explained by sympathetic nervous system activation. We cannot completely exclude chronic sympathetic stimulation and vascular remodeling. Stroke volume, on the other hand, decreased sharply in our patients, which may be due to a decrease in cardiac preload or cardiac contractility.²⁰

Several lines of evidence suggest that the autonomic nervous system contributes to hypertension in our patients. Perhaps the strongest evidence is the profound increase in blood pressure with standing. The increase was attenuated with volume loading, suggesting that the excessive increase in blood pressure was due to overcompensation of a reduction in cardiac preload. Similarly, leg compression prevents the orthostatic increase in blood pressure in patients with orthostatic hypertension.²¹ Moreover, stimuli such as cold pressor testing and hand-grip exercise led to a greater than normal pressor response. Although blood pressure responses to these stimuli were excessive, the increase in muscle sympathetic nerve activity was moderate. Thus, a smaller increase in sympathetic nerve traffic may elicit a greater pressor response.

If a smaller increase in sympathetic nerve traffic is associated with an excessive pressor response, the amount of norepinephrine with a given stimulus must be increased or the same amount of norepinephrine elicits a greater response. Plasma and urinary norepinephrine concentrations were not increased in our patients, evidence against increased norepinephrine release. Less likely is the explanation that increased norepinephrine release could be masked by changes in norepinephrine clearance.²² Therefore, the same amount of norepinephrine may elicit a greater pressor response. Indeed, our patients were extremely hypersensitive to the phenylephrine pressor response before ganglionic blockade. Ganglionic blockade can be used to study vascular responses in the absence of baroreflex-mediated changes in autonomic tone.¹¹ The fact that the sensitivity to phenylephrine was similar in patients and in control subjects during ganglionic blockade challenges the concept that increased vascular sensitivity underlies the hypersensitivity to phenylephrine.

The most likely explanation for phenylephrine hypersensitivity in our patients is impaired baroreflex buffering. The main purpose of the baroreflexes is to buffer changes in cardiac preload or vascular tone. In patients with damage to the afferent arc (baroreflex failure), the sensitivity to phenylephrine and nitroprusside is dramatically increased.²³ Similarly, impaired function of the efferent arc, due to either neuronal degeneration (autonomic failure)^{24 25 26 27} or ganglionic blockade,^{11 28 29} causes a profound increase in sensitivity to vasodilators and vasoconstrictors. In our patients, phenylephrine sensitivity was similar to the sensitivities observed in patients with baroreflex failure²³ or autonomic failure²⁴ or in control subjects during ganglionic blockade.¹¹ Furthermore, the sensitivity to phenylephrine increased only slightly during complete ganglionic blockade, suggesting that the restraining effect of the autonomic nervous system was profoundly impaired. The finding that plasma vasopressin concentration did not increase despite a marked depressor response is further evidence for impaired baroreflex function.^{30 31} We¹⁵ and others³² have shown that in healthy subjects, ganglionic blockade with trimethaphan leads to a profound baroreflex-mediated increase in vasopressin concentrations. Paradoxically, the baroreflex control of heart rate was only mildly impaired, suggesting that the baroreflex dysfunction involved primarily control of vascular tone and of vasopressin release. The wide spontaneous fluctuations in blood pressure typical for patients with baroreflex failure^{23 33} were not observed in our patients. These findings suggest that noninvasive or invasive determination of the baroreflex–heart rate slope^{34 35} does not give sufficient information on baroreflex control of vascular tone and vasopressin release.³⁶ Reliance on this parameter alone in our subjects would have led to faulty conclusions regarding their baroreceptor reflex function.

The location of the lesion to the baroreflex in our patients is difficult. Absence of orthostatic hypotension and the results of autonomic reflex testing suggest that the efferent limb of the baroreflex is at least in part intact. Impaired baroreflex-mediated vasopressin release suggests that the lesion is proximal to sympathetic efferent neurons in the rostroventrolateral medulla. Because baroreflex control of heart rate was only slightly impaired, whereas control of vascular tone was severely affected, we suggest that the lesion must be located at a place where heart rate and blood pressure control are in part separated.

All patients studied and other affected family members had a left-sided vascular PICA loop impinging on the rostroventrolateral medulla, whereas nonaffected family members had no such loops.⁴ Animal studies have shown that pulsatile compression of the rostroventrolateral medulla exerted by a balloon increases blood pressure, which may be mediated through alteration of afferent neurons traveling from baroreceptors to the nucleus tractus solitarius or through direct activation of efferent sympathetic neurons.^{8 37} Our study demonstrates that in humans, neurovascular contact of the rostroventrolateral medulla can be associated with baroreflex dysfunction and changes in sympathetic nervous system activation. However, neurosurgical decompression of the brain stem would be necessary to prove a causal relationship between neurovascular contact and baroreflex dysfunction in these patients.^{5 38 39}

We conclude that in patients with monogenic hypertension, brachydactyly, and neurovascular contact of the rostroventrolateral medulla, basal blood pressure was increased even during interruption of sympathetic and parasympathetic nerve traffic. However, sympathetic stimuli such as standing and cold pressor testing 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 the ability of the baroreflex to buffer changes in vascular tone is severely impaired in these subjects.

	Acknowledgments

 

This study was supported by a grant-in-aid from AstraZeneca, Wedel, Germany.

Received June 6, 2000; revision received July 5, 2000; accepted July 7, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Bilginturan N, Zileli S, Karacadag S, et al. Hereditary brachydactyly associated with hypertension. J Med Genet. 1973;10:253–259.[Medline] [Order article via Infotrieve]
   
2. Schuster H, Wienker TE, Bahring S, et al. Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. Nat Genet. 1996;13:98–100.[Medline] [Order article via Infotrieve]
   
3. Schuster H, Wienker TF, Toka HR, et al. Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension. Hypertension. 1996;28:1085–1092.[Abstract/Free Full Text]
   
4. Naraghi R, Schuster H, Toka HR, et al. Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly. Stroke. 1997;28:1749–1754.[Abstract/Free Full Text]
   
5. Jannetta PJ, Segal R, Wolfson SKJ. Neurogenic hypertension: etiology and surgical treatment, I: observations in 53 patients. Ann Surg. 1985;201:391–398.[Medline] [Order article via Infotrieve]
   
6. Morimoto S, Sasaki S, Miki S, et al. Neurovascular compression of the rostral ventrolateral medulla related to essential hypertension. Hypertension. 1997;30:77–82.[Abstract/Free Full Text]
   
7. Geiger H, Naraghi R, Schobel HP, et al. Decrease of blood pressure by ventrolateral medullary decompression in essential hypertension. Lancet. 1998;352:446–449.[Medline] [Order article via Infotrieve]
   
8. Jannetta PJ, Segal R, Wolfson SKJ, et al. Neurogenic hypertension: etiology and surgical treatment, II: observations in an experimental nonhuman primate model. Ann Surg. 1985;202:253–261.[Medline] [Order article via Infotrieve]
   
9. Robertson D. Pharmacology: assessment of autonomic function. In: Baughman KL, Greene BM, eds. Clinical Diagnostic Manual for the House Officer. Baltimore, Md: Williams & Wilkins; 1981:86–101.
   
10. Hokanson E. An electrical calibrated plethysmograph for direct measurement of limb blood flow. Trans Biomed Eng. 1999;22:25–29.[Medline] [Order article via Infotrieve]
    
11. Shannon JR, Jordan J, Black B, et al. Uncoupling of the baroreflex by N_N-cholinergic blockade in dissecting the components of cardiovascular regulation. Hypertension. 1998;32:101–107.[Abstract/Free Full Text]
    
12. Tank J, Baevski RM, Fender A, et al. Reference values of indices of spontaneous baroreceptor reflex sensitivity. Am J Hypertens. 2000;13:268–275.[Medline] [Order article via Infotrieve]
    
13. Schobel HP, Heusser K, Schmieder RE, et al. Evidence against elevated sympathetic vasoconstrictor activity in borderline hypertension. J Am Soc Nephrol. 1998;9:1581–1587.[Abstract]
    
14. Goldstein DS, Eisenhofer G, Stull R, et al. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest. 1988;81:213–220.
    
15. Jordan J, Shannon JR, Black BK, et al. N_N-Nicotinic blockade as an acute human model of autonomic failure. Hypertension. 1998;31:1178–1184.[Abstract/Free Full Text]
    
16. Tarazi RC, Dustan HP. Neurogenic participation in essential and renovascular hypertension assessed by acute ganglionic blockade: correlation with haemodynamic indices and intravascular volume. Clin Sci. 1973;44:197–212.[Medline] [Order article via Infotrieve]
    
17. Grassi G, Cattaneo BM, Seravalle G, et al. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31:68–72.[Abstract/Free Full Text]
    
18. Esler MD. Clinical application of noradrenaline spillover methodology: delineation of regional human sympathetic nervous responses. Pharmacol Toxicol. 1993;73:243–253.[Medline] [Order article via Infotrieve]
    
19. White M, Leenen FH. Aging and cardiovascular responsiveness to beta-agonist in humans: role of changes in beta-receptor responses versus baroreflex activity. Clin Pharmacol Ther. 1994;56:543–553.[Medline] [Order article via Infotrieve]
    
20. Aviado DM. Hemodynamic effects of ganglion blocking drugs. Circ Res. 1960;8:304–314.[Free Full Text]
    
21. Streeten DH, Auchincloss-JH J, Anderson-GH J, et al. Orthostatic hypertension: pathogenetic studies. Hypertension. 1985;7:196–203.[Abstract/Free Full Text]
    
22. Meredith IT, Eisenhofer G, Lambert GW, et al. Plasma norepinephrine responses to head-up tilt are misleading in autonomic failure. Hypertension. 1992;19:628–633.[Abstract/Free Full Text]
    
23. Jordan J, Shannon JR, Black B, et al. Malignant vagotonia due to selective baroreflex failure. Hypertension. 1997;30:1072–1077.[Abstract/Free Full Text]
    
24. Robertson D, Hollister AS, Carey EL, et al. Increased vascular beta₂-adrenoreceptor responsiveness in autonomic dysfunction. J Am Coll Cardiol. 1984;3:850–856.[Abstract]
    
25. Jordan J, Shannon JR, Biaggioni I, et al. Contrasting actions of pressor agents in severe autonomic failure. Am J Med. 1998;105:116–124.[Medline] [Order article via Infotrieve]
    
26. Mohring J, Glanzer K, Maciel JJ, et al. Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension. J Cardiovasc Pharmacol. 1980;2:367–376.[Medline] [Order article via Infotrieve]
    
27. Jordan J, Shannon JR, Pohar B, et al. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999;10:35–42.[Abstract/Free Full Text]
    
28. Page IH, McCubbin JW. Buffer reflexes, tolerance to ganglioplegics and their relationship to enhanced pressor responsiveness. Am J Physiol. 1959;197:217–222.
    
29. Haas E, Goldblatt H. Effects of various ganglionic blocking agents on blood pressure and on activity of pressor agents. J Physiol. 1960;198:1023–1028.
    
30. Kaufmann H, Oribe E, Miller M, et al. Hypotension-induced vasopressin release distinguishes between pure autonomic failure and multiple system atrophy with autonomic failure. Neurology. 1992;42:590–593.[Abstract/Free Full Text]
    
31. Zerbe RL, Henry DP, Robertson GL. Vasopressin response to orthostatic hypotension: etiologic and clinical implications. Am J Med. 1983;74:265–271.[Medline] [Order article via Infotrieve]
    
32. Baylis PH, Robertson GL. Osmotic and non-osmotic stimulation of vasopressin release. J Endocrinol. 1979;83:39P–40P.
    
33. Robertson D, Hollister AS, Biaggioni I, et al. The diagnosis and treatment of baroreflex failure. N Engl J Med. 1993;329:1449–1455.[Abstract/Free Full Text]
    
34. deBoer RW, Karemaker JM, Strackee J. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am J Physiol. 1987;253:H680–H689.[Abstract/Free Full Text]
    
35. Taylor AA. Autonomic control of cardiovascular function: clinical evaluation in health and disease. J Clin Pharmacol. 1994;34:363–374.[Abstract]
    
36. Sato T, Kawada T, Inagaki M, et al. New analytic framework for understanding sympathetic baroreflex control of arterial pressure. Am J Physiol. 1999;276:H2251–H2261.[Abstract/Free Full Text]
    
37. Morimoto S, Sasaki S, Miki S, et al. Pulsatile compression of the rostral ventrolateral medulla in hypertension. Hypertension. 1997;29:514–518.[Abstract/Free Full Text]
    
38. Jannetta PJ, Gendell HM. Clinical observations on etiology of essential hypertension. Surg Forum. 1979;30:433–435.[Medline] [Order article via Infotrieve]
    
39. Naraghi R, Gaab MR, Walter GF, et al. Arterial hypertension and neurovascular compression at the ventrolateral medulla: a comparative microanatomical and pathological study. J Neurosurg. 1992;77:103–112.[Medline] [Order article via Infotrieve]
    

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