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Home , Hypertension, Hypotension

EDITORIAL COMMITIEE

Tomas Berl, Editor William Henrich Mark PaIIer Fred Silva Denver, CO Toledo, OH Minneapolis, MN Oklahoma City, OK

DESCRIPTION OF THE TRAINING PROGRAM UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE

The Division of Nephrology. and Transplantation at the University of Florida has a distinguished faculty of 1 1 individuals who are involved in patient care. research. and teaching activities. Clinical fellows are exposed to an active diagnostic and treatment service drawing from 548 beds in Shands Hospital. 433 beds in the adjacent Gainesville Veterans Affairs Medical Center. and the facilities from both hospitals. The clinical rotations are designed to emphasize the diagnosis and management of renal and fluid and disorders. Over 100 diagnostic renal biopsies are performed each year. providing extensive experience in biopsy interpretation. The dialysis program provides fellows with the opportunity to manage acute renal failure by using a variety of techniques, including hemodialysis. hemofiltration, CAVH, and CAVHD. An outpatient chronic hemodialysis population of 70 patients and an ambulatory population of 45 patients provide practical experience in the management of ESRD requiring dialysis. The division supports an active transplant program that performs 125 transplants each year. A clinical hypertension service provides in-depth clinical and research opportunities for fellows in the field of hypertension.

Clinical and research training is a major focus of division activities. and three to four fellows are enrolled each year in the academic program of the division. Fellows are offered the opportunity to obtain research experience in one of several research laboratories in the division. The faculty can offer extensive research experience in renal physiology. renal pathology. cell biology and biochemistry. molecular biology. pharmacology. transplant immunobiology. hypertension. and related disciplines. Currently. there is also active collaboration in areas of mutual interest with faculty members in the departments of pharmacology. biochemistry and molecular biology, pathology, and physiology, and fellows have the opportunity to participate in these activities. A particularly strong aspect of our training program is the extensive one-on-one interaction fellows enjoy with the faculty in both the clinical and the laboratory seffing.

The division also offers a special 1-yr transplant fellowship that provides the trainee with an in-depth experience in all phases of solid transplantation. In addilion. the extensive inpatient and outpatient exposure to the management of transplant recipients and their donors allows the trainee to become familiar with tissue typing and organ procurement. Opportunities are also provided by the faculty for the fellows to pursue either clinical or laboratory investigation.

Extreme Pressure Fluctuations in a Patient With Intact Autonom ic Reflexes a nd Intact Sod iu m Conservation 1

Yousri M. Barn,2 Marian C. Limacher, and Christopher S. Wilcox

tion while supine or standing. In contrast, the hyper-

Y.M. Barn, 0.5. Wilcox, Division of Nephrology, Hyper- tensive episodes were associated with marked tachy- tension and Transplantation, University of Florida, cardia, sweating, , abdominal pain, and very Gainesville, FL high levels of plasma concentration. MC. Limacher, Division of , Universily of Extensive investigations failed to support a diagnosis Florida, Gainesville, FL of pheochromocyfoma. The testing of baroreceptor function and autonomic reflexes was normal. Blood (J. Am. Soc. Nephrol. 1995; 6:1347-1353) pressure was not sensitive. It was concluded that this patient has a unique clinical syndrome of ex- ABSTRACT treme fluctuation of and sympathetic A patient who had episodes of profound nervous activity yet intact cardiovascular reflexes and alternating with severe hypertension without an obvi- normal conservation. The abnormal blood ous precipitating cause is reported. The hypotensive pressure regulation most likely has a central origin. episodes were accompanied by tiredness, , Key Words: Hypotension. hypertension. autonomic. function. , and a low norepinephrine concentra- . norepinephrine

1 Received October 3, 1994. Accepted March 13, 1995. B lood pressure (BP) changes little with posture in 2 Correspondence to Dr. Y.M. Barn, Department of Medicine, Presbyterian Hos- normal human subjects because of barorefiex pifal of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231. mechanisms that adjust the sympathetic and para- 1046.6673/0605-1347103.00/0 sympathetic nervous discharge. The changes in Journal of the American Society of Nephrology Copyright © 1995 by the American Society of Nephrology rate that occur on standing up or lying down are due

Journal of the American Society of Nephrology 1347 Extreme Blood Pressure Fluctuations

for the most part to this barorefiex mechanism. Severe fundi was negative for evidence of diabetic or hyper- fluctuations in BP in the absence of changes in blood tensive . Otherwise, the examination was volume usually imply interruption in this baroreflex unremarkable including a normal neurologic exami- mechanism. For example. patients with autonomic nation. failure experience severe , sometimes accompanied by supine hypertension. The Laboratory Investigations plasma levels are normal or sup- Initial laboratory data revealed normal values for pressed. Excessive release of can oc- serum , BUN, , urinalysis, creat- cur with baroreflex failure or with mine clearance, and function tests. There was no and is associated with episodic or sustained hyperten- evidence of hypoglycemia during repeated tests, and sion. On other occasions, pheochromocytoma can most blood sugar levels ranged between 80 and 200 cause hypertension alternating with hypotension and mg/dL. . In this study, we describe a patient with episodes of hypotension alternating with hypertension Cardiac Evaluation without evidence of pheochromocytoma who has ex- She had a normal electrocardiogram, a normally treme fluctuation in plasma catecholamine levels, in- functioning pacemaker, and an echocardiogram that tact autonomic reflexes, and normal salt conserva- revealed normal cardiac valves, and normal cardiac tion. output while lying and after head-up tilt of6O degrees. CASE REPORT Neither head-up tilt nor isoproterenol infusion in- duced syncope. Clinical History Our patient is a 67-yr-old female retired book- Evaluation for Pheochromocyfoma keeper. For 1 yr. she has had intermittent episodes Plasma catecholamines were measured on several that last several days at a time of orthostatic occasions, particularly during the spontaneous epi- with syncope and falls, accompanied by weakness and sodes of hypertension and hypotension. On none of lethargy. At these times, her systolic BP is typically 55 these occasions was she taking any . The to 90 mm Hg with a of 60 to 70 beats/mm. plasma norepinephrine levels were remarkably van-

These symptoms alternate with episodes of head- able and, as shown in Figure 1 , correlated closely with aches, sweating. . anxiety, nausea, vomit- the level of systolic BP. The normal range of plasma Ing, and abdominal pain. At these times, her systolic norepinephrine is 1 10 to 700 pg/mL. When her sys- BP is typically 1 60 to 220 mm Hg with a heart rate of tolic BP was low, the plasma norepinephrine concen- 100 to 160 beats/mm. During the hypotensive or tration was frequently below the limit of normal, hypertensive episodes, there is little orthostatic fall in whereas when it was very high, it was frequenily well BP and standing is accompanied by an appropriate above the upper limit of normal. A suppres- increase in heart rate. She has required frequent sion test was performed on two occasions to further hospital admissions, averaging once a month, pre- investigate the diagnosis of pheochromocytoma (Fig- dominantly for hypotenslon. On one occasion, she had ure 2). On one occasion (during a hypotensive epi- a syncopal episode, fell, and fractured her left lateral sode), plasma norepinephrine was below normal and malleolus. She denies flushing. , visual symp- toms, , . or . She 200 was referred to our Institution for a further work-up. . In 1983, she was diagnosed to have sick sinus syn- 180 drome and a demand pacemaker was inserted. Car- . diac catheterization at that time was normal. In 1986, 160 she developed mellitus that was well con- -a.--- . trolled with therapy. One year before presen- 120 tation, she developed endocar- . ___ ditis, which was successfully treated with antibiotics. Q. 100 #{149} 00 . She is a nonsmoker, and she denies or illicit Cl) o #{149} r= +0.69 drug abuse. Her only regular medication at presenta- . n=16 p<0.01 tion was insulin (25 U of NPH in the morning and 1 2 U 60 in the evening, and 12 U of regular in the morning). . 40

Physical Examination 20 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 during the first clinic visit Plasma Norepinephrlne (pg #{149}mr1) when she was quite revealed a normal

affect, a lying BP of 156/66, a lying heart rate of 78 Figure 1 . Relationship between systolic blood pressure (SBP) beats/mm. a standing BP of 126/78. and a standing and plasma norepinephrine concentration determined on heart rate of 96 beats/mm. Examination of the optic several occasions.

1348 Volume 6 . Number 5 ‘ 1995 Barn et al

140#{149} measured while lying and after head-up tilt of 60 degrees on the last day of each study period. Urinary 130 sodium excretion was determined every 1 2 h. She C) 120 developed a sudden episode ofhypotension on the last I day of high sodium intake that required an infusion of E 110 0. 154 M saline. As shown in Figure 3, sodium reple- tion or restriction failed to alter either the lying or the ,- 100 0. tilted BP. There was a rapid and appropriate reduction in sodium excretion during the salt restriction period 90 (Figure 3). On the last study day, the effect of normal 80 saline loading on BP and heart rate was tested. Initial I lying and posthead-up tilt BP and heart rate were determined, and baseline and catechol- amine were measured. Two liters ofnormal saline was a 2 3 infused over a 2-h period. and BP and heart rate were measured again. (40 mg) was given intra- venously, and the BP and heart rate were determined 1400’ after 2 h. A urine output of 500 mL was observed over a) a 2-h period after furosemide. Two liters of normal . 1200 saline was infused again over the next 2-h period. No -C significant differences in BP or heart rate were ob- . __..1000. 800 served after normal saline infusion or furosemide administration. wE ) 600 CO. .- 400 140 120 . 200 a. 100. 0- 0- -O O 0 : 80 0 1 2 3 z -.- Standing Time after clonidine (h) 20’ -.- Lying Figure 2. Results of two clonidine suppression tests demon- n. strating changes in the systolic blood pressure (SBP) and plasma norepinephrine concentration after 0.3 mg of clonidine. remained suppressed throughout, whereas on the other occasion (during a hypertensive episode). the initial norepinephrine level was high, but was sup- pressed to normal after clonidine. A stimu- lation test was also negative. This result does not support the diagnosis ofpheochromocytoma. Further- more, whole-body computed tomographic scans (neck, chest, abdomen, and pelvis) revealed no lesion C Posftlv. Na Balance 0 f4#{149}ve Na to suggest the presence of an adrenal or extra-adrenal a U mass. Serial venous sampling from the superior and ‘CU inferior vena cava, femoral and Internal jugular , a 0 and the right atrium did not show a significant differ- a .x ence in the catecholamine levels. a C E Sodium Balance With Changes In Dietary Salt Cl) The patient was admitted to the Clinical Research Center (CRC) for 14 days to study the effects of 0 1 2 3 4 5 6 7 8 9 10 11 changes in dietary salt on sodium balance and BP. Time (days) During the first 7 days, the patient received a daily intake of 1 89 mEq of sodium, and during the following Figure 3. Heart rate (HR), systolic blood pressure (SBP), and 7 days, it was reduced to 20 mEq. The BP was sodium balance during changes In salt Intake.

Journal of the American Society of Nephrology 1349 Extreme Blood Pressure Fluctuations

Assessment of the Baroreflex Mechanism +20

Studies of the barorefiex mechanism were under- +16 taken at the CRC. During these tests, the pacemaker +12 was deactivated to properly assess the changes in -.0 heart rate. Valsalva’s maneuver was performed with +8 an intra-arterlal recording by blowing into a tube +6 connected to a pressure transducer to raise the in- 0 ‘Q +4 A SBP (mmHg) traoral pressure to 40 mm Hg for 20 s. There was a nitroprussid. . normal response of hypotension and tachycardia dur- 0’ +10 +20 +30 +40 I I I I I I I I .20 -10 ‘.. ing forced expiration. followed Immediately after the .o .o procedure by a transient overshoot ofthe BP (Figure 4) :. o, associated with bradycardla (54 compared with 1 10 ______. beats/mm). The baroreceptor reflex mechanism was I y=.0.2.0.32x I I r.-0.98 I .12 -. further evaluated by graded Infusions of phenyleph- In=9I P<#{176}.#{176}#{176}’jI

rine and . while the .16 heart rate, to Increase or decrease the systolic BP by A HR(mIn1) 25 mm Hg. respectively. was infused at a graded rate of 0. 125 to 0.75 pg/kg/per minute and Figure 5. Changes In heart rate (HR) with changes In the nitroprusside was Infused at a graded rate of 0.05 to systolic blood pressure (SBP) after phenylephrine or nitro- 1 .2 pg/kg/per minute to increase or decrease the prusside infusion as a test for the baroreflex mechanism. systolic BP by 25 mm Hg, respectively. These tests revealed appropriate Increases in heart rate during a quency and the severity of the hypotensive episodes reduction in BP and decreases in heart rate during with the use of , the hypertensive epi- increases in BP (Figure 5). sodes became more frequent than before. However, clonidine was effective In controlling these episodes. Other Investigations A drug screen was negative on three occasions. The DISCUSSION Watson-Schwartz test and the measurement of -ami- This patient presented with clinical features char- nolevulenic acid and porphobilinogen excretion for acterized by intermittent episodes of severe hypoten- were negative. Computed tomography ofthe sion associated with a slow heart rate, alternating brain and an electroencephalogram were both normal. with episodes of hypertension associated with tachy- A test was negative with a postcaptopril cardia and symptoms of catecholarn.tne excess. Some plasma activity of 2. 1 ng/mL per hour and of the diagnoses that were considered to explain the plasma of 5.5 ng/dL. Her plasma symptoms of labile hypertension with excess plasma in the morning was normal at 9.8 g/dL. catecholarnines are summarized in Table 1 . Although patients with pheochromocytoma usually present Management with intermittent or sustained hypertension, presen- The patient was treated with fludrocortisone, 0. 1 mg tatlon with hypotension or alternating hypertension twice a day, to combat hypotension and clonidine as and hypotenslon has been previously documented required to manage hypertension. Increased heart ( 13). The mechanisms of orthostatic hypotension in rate, and symptoms of catecholamine excess. Al- pheochromocytoma include reduced plasma volume, though there was a significant reduction in the fre- impaired cardiovascular reflexes, and eplnephrlne- induced vasodilatlon in blood vessels to skeletal mus- cle. In a recent review, the clonidine suppression test was found to be 92% accurate in diagnosing pheo- - chromocytoma (4). From the results of these extensive

E investigations and the favorable response to clonidine . ! treatment, pheochromocytoma appears quite un- likely. Several rare causes for this patient’s clinical condition were ruled out by appropriate evaluation 1 and include: carotid sinus syndrome, vasovagal at- a tacks, hypoglycemia, intracranial lesions or epileptic , illicit or self-administered drug use, acute intermittent porphyria, mitral valve prolapse or other 0 10 20 30 40 50 valvular lesions, renovascular hypertension. and un- derlying psychiatric disorder. Time (sec) Lesions resulting in autonomic dysfunction may Figure 4. lntra-arterial record of the blood pressure during involve the afferent pathway, the central connections, Valsava’s maneuver. the efferent pathway, the target organs, or a combina-

1350 Volume 6 ‘ Number 5 #{149}1995 Barn et al

TABLE 1 . Intermittent hypertension accompanied by Basic Work-up for Patients Suspected striking increases of plasma catecholamines of Autonomic Insufficiency

Labile Hypertension Suspected Autonomic Anxiety Insufficiency Pheochromocytoma Baroreflex Failure Damage to carotid sinuses Idiopathic DiagnosisReconsider I Insulin-Induced Hypoglycemia Intermittent Anoxia I Orthostatic 1 1 Orthostatic Drugs and I Hypotension Hypotension+ I Monoamine oxidase inhibition and tyramine t Heart+ Rate - Heart Rate Intracranial Space-Occupying Lesions I Cushing’s response _ Posterior fossa tumors Basilar I Drug 1 No Plasma Catecholamines Relevent Porphyria Intake I Drug Intermittent acute Intake F Hereditary coproporphyria Normal Normal Porphyria variegata I Low or Low or High I 1 1k k tion of these, depending on the disorder. The evalua- a.bckers. Volume depletion, Peripheral Central Old age. tion of a patient with suspected autonomic insuffi- Vasodilators Pheochromocytoma, autonomic autonomic Carotid arlery cervical cord failure, failure disease ciency includes multiple tests involving all organ transection, (Diabetes mellitus, (MSA. Prolonged bed IOH, Cerebrovascuiar systems. Therefore, the selection of the investigations rest Polyneuropathy) disease. should be designed to define the site of the lesion, Parkinson’s depending on the clinical presentation. Figure 6 de- disease) scribes a simple algorithm for the initial evaluation of Figure 6. Basic work-up for patients suspected of autonomic a patient suspected to have autonomic Insufficiency. insufficiency. IOH, idiopathic orthostatic hypotension; MSA, Further work-up will depend on the clinical presenta- multiple system atrophy. tion and the findings from the initial evaluation. Be- cause our patient had evidence of abnormal BP regu- lation, an evaluation of the autonomic control of BP intake and BP. Furthermore, no significant changes in and cardiovascular reflexes was undertaken. BP or heart rate were observed after normal saline The is required for the infusion or intravenous furosemide administration. normal regulation of body fluid. Defective renal so- Therefore, this patient does not have salt-sensitive BP, dium conservation during salt restriction was de- nor is the response to salt restriction suggestive of scribed in normal human subjects with the sympatho- autonomic neuropathy (5-7). The hypotensive epi- lytic drug guanethidmne (5). Sodium wasting was sodes cannot be ascribed to defective sodium conser- further shown In patients with autonomic failure. vation. Although the defective sodium conservation was ac- Both hypoadrenergic orthostatic hypotenslon and companied by subnormal aldosterone excretion, this hyperadrenergic orthostatic hypotension have been is only partly responsible for this defect (6). In this described in different categories of patients with dia- patient, neither lying nor standing BP fell during betes mellitus (8.9). Diabetic patients with hypoadren- sodium restriction. We studied sodium balance and ergic postural hypotension usually have combined BP in this patient during an alteration in salt intake. autonomic and peripheral neuropathy. with a lower with 1 wk of normal sodium intake followed by a week than normal mean norepinephrine concentration in of sodium restriction. As shown in Figure 3, appropri- both the supine and the standing positions ( 10). Sev- ate sodium excretion occurred during a high salt eral studies have shown an association between pe- intake and sodium conservation occurred during pe- ripheral and autonomic dysfunction in long-

nods of sodium restriction. In addition, sodium re- term insulin-dependent diabetics ( 1 1 . 1 2). The striction was not associated with postural hypoten- absence of peripheral neuropathy and other features sion or lower BP In comparison to normal sodium suggestive of autonomic neuropathy. such as gastro- intake. Indeed, the patient actually developed a hypo- intestinal symptoms or defective sweating, argues tensive episode during the high sodium Intake. against the diagnosis of diabetic autonomic neuropa- Clearly. there was no correlation between sodium thy ( 12). Furthermore, the normal response to Valsal-

Journal of the American Society of Nephrology 1351 Extreme Blood Pressure Fluctuations

va’s maneuver and appropriate heart rate changes hypotension and hypertension and the association with phenylephrmne and sodium nitroprusside infu- with changing norepinephrine concentration in our sions effectively exclude a diagnosis of autonomic patient with intact baroreflex mechanism suggest that neuropathy due to diabetes mellitus. Patients with the lesion is in the central integration of the sympa- diabetes mellitus may also have hyperadrenergic or- thetic outflow. The presence of a normal baroreflex thostatic hypotension. The increased sympathetic ac- mechanism in our patient suggests that the lesion is tivity in these patients has been attributed to a dimin- above the level of the nucleus tractus solitarli. Envi- ished Intravascular volume or a to ronmental may be translated into increased noreplnephrine (9). All patients studied had subnor- sympathetic nervous activity via the limbic-hypotha- mal , which may contribute to the ortho- lamic-bulbar autonomic centers. In addition, acute static hypotension and enhanced catecholamine 1ev- environmental stress in spontaneously hypertensive els (9). In contrast, our patient had episodes of rats elicits a prompt and sustained increase In arterial hypotension associated with low norepinephrine con- BP and heart rate (23). Our patient had no features to centrations, whereas high noreplnephrine concentra- suggest mental stress or major psychiatric illness to tions were associated with episodes oflabile hyperten- explain her clinical condition. Although it is not pos- sion. As shown in Figure 1 . the BP was directly sible to determine the exact site of lesion, the abnor- correlated with the plasma norepinephrine concentra- mal BP regulation in this patient appears to be of tion. This suggests that the high norepinephrine con- central origin. centration may be a marker of enhanced sympathetic Studies performed in this patient helped us to un- nervous system activity and may be causally related to derstand the underlying pathophysiology of her dis- the tachycardia and high BP, and not a response to a ease. The hypotensive episodes were more frequent reduced blood volume. Furthermore, our patient had and required more hospital admissions than the hy- hypertensive episodes, which are not a feature of pertensive episodes. The usual approach to the treat- hypoadrenergic or hyperadrenergic orthostatic hypo- ment of orthostatic hypotension is to expand plasma tension. Therefore, the clinical picture of this patient volume by administering fludrocortisone. Many pa- is not consistent with hypoadrenergic or hyperadren- tients with autonomic neuropathy have a normal ergic orthostatic hypotension. plasma volume (24) but may become volume ex- Baroreceptors in the carotid sinus, the aortic arch, panded during treatment with fludrocortisone. 5ev- and great vessels in the thorax transmit neural signals eral other pharmacologic agents such as prostag- via the glossopharyngeal and vagus to the landin inhibitors (25). somastostatin analogues (26). brain stem. Abnormalities in the vascular barorecep- ergot alkaloids (27), and a1- ago- tors, their neural connections, or the brain stem can nists (28) have been used with variable success and lead to baroreflex failure. True barorefiex failure en- side effects. Recently. erythropoletin has been re- tails the loss of buffering of BP and is characterized by ported to be useful in the treatment of orthostatic the volatility of BP and heart rate ( 13, 14). In a recent hypotension due to autonomic failure, although su- study, Robertson et al. described 1 1 patients with pine hypertension was a side effect in some patients barorefiex failure presenting with labile BP and hyper- (29,30). In our patient, fiudrocortisone, 0. 1 mg twice tensive episodes accompanied by high levels of plasma daily, helped to reduce the frequency of hypotensive catecholamines ( 1 5). However, our patient differs from episodes. The second aspect of the treatment of this those described previously ( 1 5-1 7), because she had patient was the hypertensive episodes associated with prominent symptomatic hypotensive episodes. More- tachycardia and elevated norepinephrine levels, over, she lacks a clinical cause, such as neck surgery, which are most likely centrally mediated. Animal for baroreceptor damage. Additionally, she had an studies have demonstrated that clonidine inhibits appropriate heart rate response to Valsalva’s maneu- central sympathetic outflow, reduces the release of ver (Figure 4) and to induced changes in BP (5). norepinephrine. and may have a vagomimetic action Therefore, this patient appears to have an intact (3 1 .32). In humans, clonidine reduced muscle sympa- baroreflex arc. thetic nerve activity and the sympathetic response to The central autonomic network is an internal regu- the cold pressor test without modifying the ability of lation system through which the brain controls viscer- the baroreceptors to respond to BP fluctuations (33). omotor, neuroendocrine, pain. and behavioral re- In our patient, clonidine suppressed norepinephrlne sponses ( 18). Bilateral lesions of the nucleus tractus concentration to normal during the clonidine sup- solitarli In experimental animals abolish the barore- pression test (Figure 2). Furthermore, clonidine was flex mechanism and result in fulminant neurogenic effective In reducing the BP and heart rate in our hypertension or chronic lability ofBP ( 19). In humans, patient during the hypertensive episodes when she intraoperative stimulation of the Insular, orbitofron- was hospitalized. Therefore, we have used initial treat- tal, or anterior temporal cortex produces substantial ment with fludrocortisone on a regular basis to reduce changes in arterial pressure and heart rate (20,21). the frequency of hypotensive episodes and clonidine Structural lesions of the frontal or prefrontal cortex intermittently to combat hypertension and tachycar- and amygdala may be associated with autonomic dia mediated by increased sympathetic outflow. disturbances (22). The sudden onset ofthe episodes of In conclusion, this patient presents with extremes

1352 Volume 6 ‘ Number 5 ‘ 1995 Barn et al

of BP without an obvious precipitating factor. The during hypotension: Evidence from direct sympathetic hypotensive episodes were associated with relative nerve recordings In humans. Circulation 1989;79:83- 92. bradycardia, tiredness, and a low norepinephrine level 14. Ferguson DW, Abboud FM, Mark AL: Relative contribu- that did not increase on standing. In contrast, the tion of aortic and carotid barorefiexes to heart rate hypertensive episodes were associated with tachycar- control in man during steady state and dynamic in- creases in arterial pressure. J Clin Invest 1985;76:2265- dia, syncope, anxiety. sweating. and very high plasma 2274. norepinephrine levels that increase further on stand- 15. Robertson D, Hoilister AS, Biaggloni I, Netterville JL, Ing. She has intact autonomic reflexes and a BP that Garcia RM, Robertson RM: The diagnosis and treatment of baroreflex failure. N Engl J Med 1993;329: 1449- appeared quite insensitive to change in salt intake. 1455. This constellation of clinical findings appears not to 16. Aksamit TR, Floras JS, Victor RG, Aylward PE: Parox- have been described before. ysmal hypertension due to sinoaortic baroreceptor den- ervatlon in humans. Hypertension 1 987;9:309-3 14. ACKNOWLEDGEMENT 17. Baun WB, Jackson A, Patton RW, Raven PB: Comparl- son of heart rate measurement protocol used during This work was supported by the Clinical Research Center at the autonomic function tests. J Appl Physiol 1981;51:516- University of Florida by Grant RR00082 from the NIH. We thank Mel 519. Fregly. PhD. who kindly undertook the catecholamine measure- 18. Benarroch EE: The central autonomic network: Func- ments, and G.F. DiBona, MD, for helpful advice on the interpretation tional organization. dysfunction and perspective. Mayo of these studies. Clin Proc 1993;68:988-100l. 19. Reis DJ: The brain and hypertension: reflections on 35 years of inquiry into the neurobiology of the circulation. REFERENCES Circulation 1984;70(Suppl 31:11131-11145.

1 . Stein PP, Black HR: A simplified diagnostic approach to 20. Oppenheimer SM, Gelb A, Girvin JP. Hachinski VC: pheochromocytoma. A review of the literature and report Cardiovascular effects of human insular cortex stimula- of one institution’s experience. Medicine 1991 ;70:46- tion. Neurology 1992;42:1727.-l732. 66. 2 1 . Chapman WP. Livingston RB, Livingston KE: Frontal 2. Baxter MA, Hunter P. Thompson GR, London DR: Pheo- lobotomy and electrical stimulation of orbital surface of chromocytoma as a cause of hypotension. Clin Endocri- frontal lobes. Arch Neurol Psychiatry l949;62:70l-.716. nol 1992;37:304-306. 22. Loewy AD. Central autonomic pathways. In: Loewy AD. 3. Ganguly A, Grim CE, Weinberger MH, Henry DP: Rapid Spyer KM. Eds. Central regulation of Autonomic Func- cyclic fluctuations of blood pressure associated with an tions. New York: Oxford University Press; 1990:88-103. adrenal pheochromocytoma. Hypertension 1984;6:28 1- 23. Dibona GF: Stress and sodium intake in neural control 284. of renal function in hypertension. Hypertension 1991; 4. Sjoberg lu. Simcic KJ. Kidd GS: The clonidine suppres- 1 7lSuppl 1111:1112-1116. sion test for pheochromocytoma. A review of its utility 24. Wilcox CS. Body fluids and renal function in autonomic and pitfalls. Arch Intern Med J 1992; 152:1193-1197. failure. In: Bannister R, Ed. Autonomic Failure: A Text- 5. Gill JR, Banter FC: Adrenergic nervous system in so- book of Clinical Disorders of the Autonomic Nervous

dium . 1 1 . Effect ofguanethidine on the renal System. 1st Ed. Oxford: Oxford University Press; 1983: response to sodium deprivation in normal man. N Engl J 115-154. Med 1996;275: 1466-1471. 25. Ahmad RAS, Watson RDS: Treatment of postural hypo- 6. Wilcox CS, Aminoff MJ, Slator JDH: Sodium homeosta- tension. A review. Drugs 1990;39:74-85. sis In patients with autonomic failure. Clin Sci Mol Med 26. Hoeldtke RD. Davis KM: The orthostatic tachycardia 1977;53:32 1-328. syndrome: Evaluation of autonomic function and treat- 7. DiBona GF, Wilcox CS. The kidney and the sympathetic ment with and ergot alkaloids. J Clin Endo- nervous system. In: Bannister R. Mathias CJ. Eds. Au- crinol Metab 1991;73:132-139. tonomic Failure: A Textbook of Clinical Disorders of the 27. Biaggioni I. Zygmunt D, Ha.ile J, Robertson D: Pressor Autonomic Nervous System. 3rd Ed. Oxford: Oxford effect of Inhaled ergotamine In orthostatic hypotension. University Publication; 1992:178-196. Am J Cardlol l990;65:89-92. 8. Cryer PE, Silverberg AR, Santiago JV, Shah SD: Plasma 28. Jankovinc J, Gilden JL, Hinner BC, et aL: Nuerogenic catecholamines in diabetes: The syndrome of hypoadren- orthostatic hypotension: A double-blind, placebo- ergic and hyperadrenergic postural hypotension. Am J controlled study with . Am J Med l993;95:38- Med 1978;64:407-416. 48. 9. Tomeh W, Shah SD, Cryer PB: The pathogenesis of 29. Hoeldtke RD. Streeten DH: Treatment of orthostatic hyperadrenergic postural hypotension in diabetic pa- hypotension with erythropoietln. N Engi J Med 1993; tients. Am J Med l979;67:772-778. 329:61 1-6 15. 10. Christensen NJ: Plasma catecholamines in long-term 30. Biaggioni I, Robertson D, Krantz S. Jones M, Haile V: diabetics with and without neuropathy and in hypoph- The of primary autonomic failure and its reversal ysectomlzed subjects. J Clin Invest 1972;51:779-787. with recombinant erythropoietln. Ann Intern Med 1994; 1 1 . Ziegler D, Cicmir I. Wiefels K. Berger H, Gries FA: 121: 181-186. Peripheral and autonomic nerve function in long-term 3 1 . Maze M, Tranquilli W: cx2-Adrenoceptor agonists: Defin- insulin-dependent diabetes. Diabetes Res J l987;4:9- Ing the role in clinical anaesthesia. Anesthesiology 1991; 14. 74:581-605. 12. Ziegler D, Dannehl K, Muhlen H, Spuler M, Gries FA: 32. Kobinger W, Walland A: Investigations Into the mecha- Prevalence of cardiovascular autonomic dysfunction as- nism of the hypotensive effect of 2-(2.6 dichlorphe- sessed by spectral analysis. vector analysis. and stan- nylamino)-2-imidazollne-HCL. Eur J Pharmacol l967;2: dad tests of heart rate variation and blood pressure 155-162. responses at various stages of . Di- 33. Muzi M, Goff DR. Kampine JP, Roerig DL, Ebert TJ: abetes Med 1992;9:806-814. Clonidine reduces sympathetic activity but maintains 13. Sanders JS, Mark AL, Ferguson DW: Importance of baroreflex responses in normotensive humans. Anesthe- aortic barorefiex in regulation of sympathetic responses siology 1992;77:864-871.

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