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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.1.11 on 1 January 1977. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry, 1977, 40, 11-19 Idiopathic orthostatic hypotension from failure of noradrenaline release in a patient with vasomotor innervation R. N. NANDA,1 F. C. BOYLE, J. S. GILLESPIE, R. H. JOHNSON,2 AND H. J. KEOGH From the University Department ofNeurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, and the University Department ofPharmacology, Glasgow SUMMARY A 26 year old man is described with life-long orthostatic hypotension unrelated to autonomic nerve degeneration and apparently due to failure ofperipheral noradrenaline release. Tests of parasympathetic and sympathetic cholinergic nerve function were normal, but sympathetic adren- ergic activity was defective. Thus blood pressure regulation was abnormal. There was no pressor response to tyramine, an indirect sympathomimetic drug, but a marked pressor response to the directly acting sympathomimetic drugs phenylephrine and noradrenaline. On standing there was a guest. Protected by copyright. progressive fall rather than a rise in circulating noradrenaline concentrations, although adrenaline levels rose normally. The pupils showed diminished responses to ephedrine and cocaine, and a normal response to phenylephrine. Fluorescence microscopy of blood vessels showed that they were in- nervated with adrenergic nerves. His orthostatic hypotension responded well to oral phenylephrine (50 mg five times daily) but not to other forms of therapy. It is suggested that this patient's symptoms were due to failure of noradrenaline release even though sympathetic adrenergic nerves were present. We therefore wish to draw attention to a further cause oforthostatic hypotension, failure ofperipheral noradrenaline release without autonomic neuropathy. Orthostatic hypotension may occur either as an idio- Case report pathic disorder or as a complication of many neuro- logical disorders (Johnson and Spalding, 1974, 1976). CLINICAL HISTORY The lesion may be in the afferent or efferent pathways, The patient (A. M., Institute of Neurological or in the central nervous system connections of the Sciences, Glasgow, 816955) complained of'blackouts' baroreceptor reflex arc controlling vasoconstriction. from early childhood, at least since the age of 5 years. Reduced noradrenaline excretion has been reported During the blackouts, which always occurred when in patients with idiopathic orthostatic hypotension standing, he had greying of vision, and would then http://jnnp.bmj.com/ (Luft and von Euler, 1953; Barnett et al., 1955; frequently collapse unconscious for a few seconds. He Hickler et al., 1959), and some of these patients lack had been unable to participate in games involving the fluorescent fibres characteristic of sympathetic standing and running. He found that if he stood in a vasomotor innervation (Kontos et al., 1975). We now stooped manner, crossed his legs, or leant against a report a patient with idiopathic orthostatic hypo- wall, symptoms were less frequent, and he adopted tension who also had failure of peripheral nora- this posture as a habit. He attended school until the drenaline release, but biopsy studies demonstrated age of 15 years, and had earned his living as a bar that he had adrenergic innervation of blood vessels. tender. He had been married for two years and on September 27, 2021 by complained of impotence which had resulted in serious marital strife. He had normal penile erection, but there was no ejaculation. His past medical history 'Address for correspondence: Dr R. N. Nanda, Department of was non-contributory, he was an only child, and his Medicine, Clinical Medical School, Wellington Hospital, Wellington 2, New Zealand. parents were alive and well. The parents' marriage 2Present address as in'. was not consanguineous. He smoked over 20 cigar- Accepted 30 August 1976 ettes daily and drank alcohol in moderation. 11 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.1.11 on 1 January 1977. Downloaded from 12 R. N. Nanda, F. C. Boyle, J. S. Gillespie, R. H. Johnson, and H. J. Keogh On examination he was thin, with an asthenic resting levels. The procedure was repeated on three build, and pale but not obviously anaemic. He had a occasions within half an hour (Fig. 1). Arterial blood marked kyphosis. His height was 171.5 cm and his was sampled at the end of each tilt for estimation of weight was 59 kg. Blood pressure when lying was circulating adrenaline and noradrenaline concentra- 127/70 mmHg, with pulse rate of 64 beats/min; on tions (Valori et al., 1970; Rennie, 1974). The resting standing the blood pressure became unrecordable levels ofnoradrenaline and adrenaline were 2.2 nmol/l within one minute. Neurological examination, and 0.25 nmol/l respectively. During the investigation, including tendon reflexes, was normal. External adrenaline levels rose to a maximum of 1.1 nmol/l. genitalia and secondary sexual characteristics were The noradrenaline levels, however, fell, instead of also normal. rising, so that during the final tilt there was no measurable noradrenaline in the circulating blood. INVESTIGATIONS The following investigations were normal: ESR, Valsalva's manoeuvre haemoglobin, differential white cell count, blood After a deep inspiration, the patient attempted a urea and electrolytes (sodium, potassium, chloride, forced expiration for 10 seconds through a face mask calcium and phosphate), alkaline phosphatase, bili- connected by a thick-walled rubber tube to a strain rubin and flocculation tests, B12, Wassermann gauge manometer and anaeroid manometer which the reaction, glucose tolerance test, urine excretion of patient observed. The strain gauge manometer was 17-ketosteroids (68.4 timol/24 h) and 17-hydroxy- attached to a chart recorder (Elema Sch6nander corticosteroids (55.9 ,tmol/24 h), urinary excretion of Mingograph). The patient was asked to maintain a porphyrins (nil). Cerebrospinal fluid had normal pressure of 30-40 mmHg for the 10 s period. The findings for protein, cells and glucose. Urinary blood pressure fell progressively during the man- guest. Protected by copyright. metadrenaline output was normal (2.2 Htmol/24 h), oeuvre and a tachycardia developed (67 beats/min to and urinary vanillylmandelic acid output was low 83 beats/min) but there was no overshoot of blood (6.6 ttmol/24 h, normal range 10-35 ttmol/24 h). pressure after intrathoracic pressure returned to normal (a 'blocked response', Johnson and Spalding, AUTONOMIC FUNCTION 1974). As the blood pressure returned to normal, the Change ofposture heart rate was reduced to the original level. On the morning of the investigation of arterial blood pressure responses, the patient stayed in bed and was Heart rate changes with drugs and respiration taken to the laboratory and then transferred onto a Intravenous atropine sulphate (3 mg) increased the tilt table. The arterial blood pressure was recorded patient's heart rate from resting values in the range of with a catheter in the brachial artery. The catheter 53-60 to 98-102 beats/min. No further increase in was connected to a strain gauge manometer recording heart rate could be obtained when orthostatic hypo- system (Elema-Schonander) with the manometer tension was induced by tilting. After the administra- fixed at the mid-sternal level. Its calibration was tion ofatropine, propranolol (0.2 mg/kg body weight) checked before and at the end of each investigation produced no further significant change in heart rate and when the patient's posture was changed. Heart (even in the presence of orthostatic hypotension rate was recorded continuously during the investiga- produced by tilting). During deep breathing, the tion with an electrocardiograph. Intravenous infus- patient showed normal sinus arrhythmia which was ions were administered from a motor driven syringe abolished by atropine (Wheeler and Watkins, 1973). http://jnnp.bmj.com/ through a 22 gauge cannula inserted under local anaesthesia into an antecubital vein in the opposite Sudden noise and mental arithmetic arm to that into which the blood pressure catheter A starting pistol was fired immediately behind the had been inserted. Blood pressure and heart rate were patient without causing a rise in blood pressure. A observed while the patient's posture was changed and simple standard test of addition and subtraction other tests were performed. failed to produce a rise of blood pressure. Both these The patient was moved from the supine to the erect tests usually cause a rise of blood pressure in normal position. The blood pressure when he was supine was subjects (Johnson and Spalding, 1974). on September 27, 2021 by 110/70 mmHg, and it fell when he was in the erect position (850) to 65/45 mmHg within one minute. The Infusion ofdrugs (Fig. 2) heart rate was 64 beats/min in the supine position and L-noradrenaline was infused at progressively in- increased to 98 beats/min one minute later. The creasing rates of2, 4, 6, and 8 jig/min, each level being patient complained of feeling faint and was returned maintained for one minute. At the highest infusion to the horizontal position. The systolic and diastolic rate, the blood pressure rose to 200/100 mmHg, and pressures rose again, but did not exceed the original the heart rate decreased to 40 beats/min. Similar J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.1.11 on 1 January 1977. Downloaded from Idiopathic orthostatic hypotension from failure ofnoradrenaline release 13 120 - M Standing 100 - Blood Pressure 80 - ( mmHg) 60 - 40 - 100 - Heart Rate 80 - Fig. 1 Response to repeated ( beats/ min ) standing (M) on bloodpressure, 60 - -- heart rate, andplasma catecholamines ( x - x x noradrenaline, 0-0 2-0 - adrenaline). x NA guest. Protected by copyright. 15 - x Catechol - amines 1 0 - (n mot/Il) 0 5 - x 0 - x 0 10 20 30 40 TIME ( min ) results were obtained with infusion of phenylephrine as the slope of the graph relating the pulse interval at measured rates of between 60 and 200 ,ig/min.

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