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(Hypertension. 1996;28:42-46.)
© 1996 American Heart Association, Inc.
Articles |
Orthostatic Hypertension Due to Vascular Adrenergic Hypersensitivity
the Clinical Pharmacology (N.L.B., S.Z., S.C.), Endocrinology (M.S.), and Cardiology (J.W., M.C.) Units of the Medical Service, San Francisco General Hospital Medical Center, University of California, San Francisco.
Correspondence to Neal L. Benowitz, MD, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, Box 1220, San Francisco, CA 94143-1220. E-mail nbeno@itsa.ucsf.edu.
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Abstract |
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 Top Abstract IntroductionCase Report and MethodsResultsDiscussionReferences |
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Autoregulatory mechanisms ensure relatively small fluctuations of blood pressure with postural changes in healthy people. Although orthostatic hypotension is well recognized and commonly encountered, there are only a few reports of orthostatic hypertension. Most of the reported cases of orthostatic hypertension were related to excessive venous pooling, with an initial drop in cardiac output followed by overcompensation with an excessive release of catecholamines, or to nephroptosis with orthostatic activation of the renin-angiotensin system. We describe a 44-year-old woman with normal supine blood pressure and severe orthostatic hypertension who did not demonstrate an initial decrease in cardiac output and had normal plasma and urinary catecholamines and renin release. Pharmacological tests of autonomic nervous system function showed an increased pressor sensitivity to norepinephrine (11 to 14 times normal), normal sensitivity to isoproterenol, diminished baroreceptor reflex sensitivity, and exquisite sensitivity to
-adrenergic blockers. This unusual case of orthostatic hypertension appears to be secondary to vascular adrenergic hypersensitivity.
Key Words: posture • hypertension, orthostatic • vascular resistance
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Introduction |
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TopAbstractIntroductionCase Report and MethodsResultsDiscussionReferences |
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Normally, blood pressure (BP) fluctuates only minimally with postural changes because of autoregulatory mechanisms.1 Some orthostatic increase in diastolic BP occurs, particularly in hypertensive patients, and is due to an increase in vascular resistance.2 A subset of patients with essential hypertension has an increased sympathetic activity.3 4 5
Orthostatic hypotension is commonly encountered and its physiology has been well characterized,5 6 but there are few reports of orthostatic hypertension. In one group of 181 patients with orthostatic hypertension, defined as an orthostatic rise in diastolic BP above 90 mm Hg with supine diastolic BP below 90 mm Hg, 12 were studied; their orthostatic hypertension was related to excessive venous pooling, which resulted in decreased cardiac output followed by an excessive rise in plasma catecholamines, leading to vasoconstriction.7 There are two reports of renal orthostatic hypertension related to nephroptosis and postural activation of the renin-angiotensin system.8 9 Sapru et al10 reported on a man in whom transient orthostatic hypotension preceded the orthostatic rise in BP. Autonomic evaluation demonstrated diminished baroreflex sensitivity and an exaggerated pressor response to the cold pressor test and Valsalva phase 2. Combined autonomic blockade with propranolol and atropine abolished the postural BP changes. These data suggested that the exaggerated pressor response was due to an increase in systemic vascular resistance in excess of the demands arising from a transient postural fall in cardiac output.
Araki et al11 described a 75-year-old woman with orthostatic hypertension. Her evaluation included measurements of plasma renin activity and aldosterone and norepinephrine levels, which were normal and demonstrated a normal response to standing; she also had normal heart rate and BP responses to intravenous phenylephrine and phentolamine, isoproterenol, propranolol, and atropine. They concluded that she had decreased parasympathetic and ß-adrenergic tone with increased ß- and -adrenergic sensitivity.
We describe a patient with normal supine BP and marked orthostatic hypertension without transient orthostatic hypotension. Her orthostatic hypertension appears to be secondary to vascular hyperresponsiveness to endogenous pressor stimuli.
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Case Report and Methods |
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A 44-year-old white woman was first noted to have high BP on a routine examination 14 years before admission. Subsequent BP measurements were taken with the patient in a supine position and were in a normal range. Three years before admission, the patient noted a gradual onset of fatigue, dizziness, shortness of breath, and headaches. At this time, her sitting BP values were 180 to 200/100 to 114 mm Hg. She was treated with hydrochlorothiazide and propranolol, and although her hypertension was moderately well controlled, she complained of chest pain, dizziness, and weakness, necessitating discontinuation of her treatment. Her evaluation included electrocardiography and lung scan, which were normal, and echocardiogram and cardiac catheterization, which showed mild mitral valve prolapse with normal coronary arteries, no left ventricular hypertrophy, and no mitral regurgitation. Treadmill exercise test was normal. She tried a variety of antihypertensive agents, including clonidine, prazosin, metoprolol, atenolol, hydralazine, and captopril, but each had to be discontinued as a result of disabling side effects. In particular, prazosin in a therapeutic dose of 2 mg resulted in a BP of 80/60 mm Hg and near-syncope. Of note is the fact that the patient had a history of intolerance to over-the-counter "cold" medications, resulting in headache, dizziness, and blurred vision. Urinary 4-hydroxy-3-methoxymandelic acid and 5-hydroxyindoleacetic acid were normal, and renal arteriography showed a sharply angulated but not stenotic left renal artery with a prolonged arterial phase. At this time, it was first noted that the patient's BP was normal when she was recumbent but would increase to hypertensive levels after she sat up or stood. She was admitted to the General Clinical Research Center at San Francisco General Hospital for further evaluation of orthostatic hypertension.
Her history was unremarkable. Family history was notable for a father, mother, and son with hypertension and three parental relatives with kidney disease. On physical examination, her weight was 61.4 kg; height, 165 cm; and BP, 110 to 120/80 to 90 mm Hg, with heart rate of 70 beats per minute (bpm) while supine, and 170 to 180/100 to 110 mm Hg and 85 bpm after standing. Fundi showed mild arteriolar narrowing. Cardiac exam revealed an S4 and grade 1/6 apical systolic murmur with intermittent nonejection systolic click. Serum chemistries, blood count, urinalysis, electrocardiogram, and chest radiograph were normal. Thyroid function test and 24-hour urinary 4-hydroxy-3-methoxymandelic acid were repeated and were normal. Urinary aldosterone levels were appropriate for the corresponding 24-hour urinary electrolytes. Aldosterone excretion rose from 29 to 137 to 174 nmol/d, with corresponding urinary sodium excretion of 124, 10, and less than 5 mEq/24 h. Renal vein catheterization was performed for measurement of differential renal vein renin activity in the supine and upright (45°) positions. Postural change elicited the typical rise in BP and heart rate from 144/90 mm Hg and 64 bpm to 174/118 mm Hg and 100 bpm. Renin levels were normal and showed no lateralization in response to the position change.
Infusion Studies
To determine whether the patient had an increased responsiveness to catecholamines, we studied pressor responses to norepinephrine with the patient in the supine position. Norepinephrine was infused at rates of 5, 10, 25, 50, and 100 ng/kg per minute for 10 minutes each, and BP levels were recorded. The pressor dose was determined as the infusion rate of norepinephrine required to produce a 30% increase in systolic BP. With the patient supine, angiotensin II (Ang II) was infused at rates of 0.05, 0.1, 0.2, 0.5, and 1.0 ng/kg per minute for 6 minutes each. The pressor dose was calculated as the amount of Ang II required to produce an increase in diastolic BP of 20 mm Hg. ß-Adrenergic responsivity was studied by rapid intravenous injections of 0.1, 0.2, 0.4, 0.8, and 1.6 µg isoproterenol. ß-Adrenergic sensitivity was expressed as the dose required to increase heart rate by 25 bpm.
Pharmacological Blockade Studies
To assess the role of angiotensin in the postural BP response, we infused saralasin ([Sar1,Ala8]Ang II) at 0.04 and 10 µg/kg per minute with the patient in the supine and standing positions. Intravenous injections of 4 and 8 µg/kg phentolamine, 0.15 mg/kg propranolol, and 8 and 17 µg/kg atropine were administered with the patient supine and sitting. BP and heart rate were recorded before and after each injection.
Baroreceptor Reflex Studies
During cardiac catheterization, bolus injections of 10 and 20 µg phenylephrine and 20, 40, 80, and 150 µg nitroglycerin were administered with the patient supine. Systolic BP from the time of injection to the highest or lowest level after injection was plotted versus the RR interval following it. Baroreceptor sensitivity was expressed as a change in RR interval (milliseconds) over the change in systolic BP (millimeters of mercury). Pressor sensitivity was defined as a change in systolic BP per 100 µg phenylephrine. Physiological studies during cardiac catheterization included carotid sinus massage, sustained handgrip, Valsalva maneuver, and bicycle exercise in supine and sitting positions. Three to 4 minutes were allowed between the tests to allow BP and heart rate to return to baseline.
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Results |
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TopAbstractIntroductionCase Report and MethodsResultsDiscussionReferences |
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BP Response to Postural Change
BP measurements were continuously recorded by an intra-arterial catheter. A typical BP response to positional change was from 140/80 supine to 190/110 sitting to 205/120 mm Hg standing. The BP rise occurred immediately after positional change, with no initial drop in BP. The pressure plateaued in less than a minute and persisted as long as upright posture was maintained. Hemodynamic studies performed during cardiac catheterization corresponding to BP measurements demonstrated no significant change in cardiac output, with an increase in systemic vascular resistance with postural change (Table 1
). No transient drop in BP or cardiac output was observed. These data suggest that the postural hypertension was produced by a primary increase in systemic vascular resistance and was not a response to a transient reduction in cardiac output.
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Catecholamine Response to Postural Change
To investigate the possibility of excessive catecholamine release as a cause for hypertension, we measured venous plasma norepinephrine and epinephrine levels. The levels were within a normal range and demonstrated an appropriate increase when the patient was standing: With the patient at rest in the supine position for 30 minutes and standing for 5 and 10 minutes, norepinephrine levels were 0.96, 1.60, and 1.59 nmol/L (164, 272, and 270 pg/mL; normal at rest, 0.66 to 3.88 nmol/L), respectively, and epinephrine levels were 71, 76, and 49 pmol/L (13, 14, and 9 pg/mL; normal at rest, <272 pmol/L). Urinary 24-hour catecholamine levels were also within a low normal range: norepinephrine, 295 nmol (50 µg); epinephrine, 8.7 nmol (1.6 µg); normetanephrine, 1.5 µmol (285 µg); and metanephrine, 0.6 µmol (114 µg).
Infusion Studies
The pressor dose of norepinephrine required to raise the patient's systolic BP by 20 mm Hg was 10 ng/kg per minute, whereas in healthy subjects the required dose is 140 ng/kg per minute and in hypertensive subjects the dose is 87 ng/kg per minute.12 13 The dose required to raise BP by 30% was 22 ng/kg per minute, with the dose for healthy subjects being 251 ng/kg per minute.14 Thus, our patient had a pressor sensitivity to norepinephrine 11 to 14 times that of normal. The pressor dose of Ang II, calculated as the amount of Ang II required to produce an increase in diastolic BP of 20 mm Hg, was 0.35 ng/kg per minute. The reported mean pressor dose for healthy subjects is 7.4 to 9.1 ng/kg per minute.15 16 Our patient had a 20-fold increase in pressor sensitivity for Ang II. Her isoproterenol sensitivity was 1.14 µg, which is within the normal range.17 18
Pharmacological Blockade Studies
While supine, the patient exhibited a mild pressor response to 10 µg/kg per minute saralasin. However, upon standing, her hypertensive response was not blunted (BP and heart rate changed from 144/98 mm Hg and 60 bpm to 176/122 mm Hg and 84 bpm). This finding suggests that orthostatic hypertension in this patient was not renin-angiotensin dependent. Intravenous injection of 4 µg/kg phentolamine lowered her BP from 170/95 to 155/85 mm Hg and increased her heart rate from 96 to 108 bpm. A dose of 8 µg/kg caused a more dramatic fall in BP, from 145/80 to 115/75 mm Hg, and precipitated chest pain. Administration of 0.15 µg/kg propranolol IV did not blunt the postural hypertensive response but slowed heart rate appropriately from 108 to 84 bpm when the patient was supine and to 70 bpm when sitting. Subsequent atropine injection of 8 and 17 µg/kg resulted in tachycardia, mild supine elevation of BP, and blunting of the postural hypertensive response (145/85 mm Hg, 68 bpm at baseline; 159/90 mm Hg, 90 bpm after atropine; 155/90 mm Hg, 100 bpm after standing).
Baroreceptor Reflex Studies
Injection of 20 µg phenylephrine resulted in a baroreflex sensitivity index of 5.82 ms/mm Hg. The reported values for normotensive control subjects are 9.9±5.4 and 13.2±8.1 ms/mm Hg19 20 and for hypertensive subjects is 7.37±5.05 ms/mm Hg. Injection of 40 and 80 µg nitroglycerin resulted in baroreflex indexes of 3.9 and 3.3 ms/mm Hg, similar to the values found in hypertensive subjects (3.7 ms/mm Hg) and lower than those seen in healthy control subjects (8.4 ms/mm Hg).20 The pressor sensitivity to phenylephrine, defined as the change in systolic BP per 100 µg of drug, was 360 mm Hg, which is 22 times that of normotensive subjects (17 mm Hg) and 10 times that of hypertensive subjects (36 mm Hg).20 The depressor response after 80 µg nitroglycerin was three times greater than that of normotensive control subjects (25 mm Hg) and hypertensive subjects (36 mm Hg).20 There was no response to carotid sinus massage with the patient supine or sitting.
Supine Valsalva maneuver resulted in a normal decrease of BP from 145/80 to 115/100 mm Hg followed by an appropriate overshoot after release (190/100 mm Hg, Table 2). Corresponding heart rates were 84, 120, and 72 bpm, respectively. When the Valsalva maneuver was done with the patient sitting, BP dropped from 165/70 to 100/80 mm Hg and increased to 205/90 mm Hg after release. Concomitant changes in heart rate were 72, 108, and 96 bpm, respectively. The reflex cardiac slowing was appropriate while the patient was supine but was blunted when she was sitting. Also, mean arterial BP fell during strain in the sitting but not supine position.
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Exercise Response
Sustained handgrip exercise increased BP from 140/75 to 160/90 mm Hg and heart rate from 75 to 90 bpm while the patient was supine and from 135/75 to 195/102 mm Hg and 84 to 102 bpm while sitting (Table 2
). Supine bicycle exercise resulted in a rise in BP from 145/85 to 185/100 mm Hg, a rise in heart rate from 80 to 114 bpm, an increase in cardiac output from 6.2 to 10.1 L/min, and a fall in systemic vascular resistance index from 1329 to 887 dyne·s/cm5 (Table 3). Upright bicycle exercise resulted in a fall in diastolic BP and less of a rise in systolic BP (160/90 to 175/80 mm Hg), an increase in cardiac output from 5.2 to 10.1 L/min, and a fall in systemic vascular resistance from 1692 to 871 dyne·s/cm5.
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Pharmacological Trials
A variety of therapeutic agents were given to the patient, and although most were successful in alleviating the postural hypertensive response, they had to be discontinued after incapacitating side effects (Table 4). Notably, even minute doses of -blockers, such as 2.5 µg prazosin every 3 to 4 days, were effective in abolishing postural hypertension but produced intolerable side effects of dizziness, fatigue, and headache.
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Discussion |
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TopAbstractIntroductionCase Report and MethodsResultsDiscussionReferences |
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Orthostatic hypertension has been described in patients with nephroptosis8 9 and in patients with excessive venous pooling and reduction in cardiac output or with initial orthostatic hypotension.7 10 There is one report of a patient in whom the mechanism of orthostatic hypertension seems to be both
- and ß-adrenergic hypersensitivity.11 Our patient did not have even a transient drop in BP or cardiac output on standing, as demonstrated by continuous intra-arterial BP monitoring. The mechanism of orthostatic hypotension in our patient seemed to be an exquisitely hypersensitive vascular responsiveness to endogenous vasoconstrictors. This was evidenced by an increased pressor sensitivity to norepinephrine and phenylephrine as well as Ang II, while plasma and urinary catecholamine levels were normal. Sensitivity to endogenous vasoconstrictors was suggested by a marked orthostatic increase in systemic vascular resistance. The withdrawal of vagal tone on assumption of the upright position also appeared to play a role, because its blockade with atropine (with a resultant increase in supine BP) abolished the orthostatic hypertension response. Interestingly, during exercise in an upright position, there was no hypertension, probably because vasodilatation in skeletal muscle and the subsequent drop in systemic vascular resistance were enough to prevent the rise in BP. Her exquisite sensitivity to very small doses of -blockers such as prazosin supports the proposed mechanism of her orthostatic hypertension. Even though the patient exhibited hypersensitivity to Ang II, the renin-angiotensin system did not seem to play a significant role in her hypertension because saralasin failed to blunt the orthostatic hypertensive response and differential renal vein renin levels were normal, with appropriate responses to positional change. Exaggerated responses to catecholamines are well known in patients with autonomic failure and are thought to be a result of denervation hypersensitivity.5 21 Some hypertensive patients, as well as normotensive offspring of hypertensive parents, have an increased sensitivity to pressor agents with normal circulating levels of catecholamines, but no orthostatic increase in BP has been reported in these cases.3 4 5
Some women with mitral valve prolapse have increased sympathetic activity, usually manifesting as orthostatic tachycardia. In such cases, high orthostatic levels of catecholamines with increased ß-sensitivity are usually found.18 23 24 Our patient had normal catecholamine levels and increased - but not ß-sensitivity. Some of her symptoms, such as fatigue, dizziness, and chest pain, can be explained by mitral valve prolapse, but it does not explain her orthostatic hypertension. Our patient had a decrease in baroreceptor sensitivity, as evidenced by a phenylephrine test and the lack of appropriate pulse reduction during the release phase of the Valsalva maneuver. This phenomenon has also been described in patients with hypertension,25 although it is not clear whether it has a causative role in or is a result of hypertension. At last examination, despite continued orthostatic hypertension, the patient had no complications related to uncontrolled hypertension. The only eye-ground changes were limited to mild arteriolar narrowing. Because of intolerable side effects, the patient declined further treatment with sympatholytic or vasodilator drugs and was treated with diuretics that did not adequately control the orthostatic hypertension.
In summary, we describe a patient with marked orthostatic hypertension, which seems to be mediated by vascular hyperresponsiveness to sympathetic activation. The patient's BP could be lowered by any vasodilator but was particularly sensitive to minute doses of -blockers. The lowering of orthostatic hypertension was not well tolerated by the patient and produced symptoms usually seen with orthostatic hypotension, such as dizziness, headache, and chest pain. The patient differs from other reported cases of orthostatic hypertension in the literature. It is important to be aware of this phenomenon, because it can be missed if BP is measured only with the patient in a supine or sitting position.
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Acknowledgments |
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This research was carried out in the General Clinical Research Center at San Francisco General Hospital with support of the Division of Research Resources, National Institutes of Health (RR-00083).
Received December 11, 1995; first decision February 6, 1996; accepted February 6, 1996.
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