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Dysautonomia (autonomic dysfunction) occurs in the Ehlers–Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.

The symptoms of joint hypermobility extend beyond articular pain. Hypermobile people commonly experience autonomic symptoms (dysautonomia), and anxiety or related psychological issues. We tested whether dysautonomia might mediate the association between hypermobility and anxiety in adults diagnosed with mental health disorders and/or neurodevelopmental conditions (hereon referred to as patients), by quantifying joint hypermobility and symptoms of autonomic dysfunction. Prevalence of generalized joint laxity (hypermobility) in 377 individuals with diagnoses of mental health disorders and/or neurodevelopmental conditions was compared to prevalence recorded in the general population. Autonomic symptom burden was compared between hypermobile and non‐hypermobile patients. Mediation analysis explored relationships between hypermobility, autonomic dysfunction, and anxiety. Patient participants had elevated prevalence of generalized joint laxity (38%) compared to the general population rate of 19% (odds ratio: 2.54 [95% confidence interval: 2.05, 3.16]). Hypermobile participants reported significantly more autonomic symptoms. Symptoms of orthostatic intolerance mediated the relationship between hypermobility and diagnosis of an anxiety disorder. Patients with mental health disorders and/or neurodevelopmental conditions have high rates of joint hypermobility. Accompanying autonomic dysfunction mediates the association between joint hypermobility and clinical anxiety status. Increased recognition of this association can enhance mechanistic understanding and improve the management of multimorbidity expressed in physical symptoms and mental health difficulties.

To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH).

Postural tachycardia syndrome (PoTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms—palpitations, dizziness and occasionally syncope—mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers–Danlos syndrome hypermobility type, formerly termed Ehlers–Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of PoTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments.

(6R)-5,6,7,8-Tetrahydro-L-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans.

Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

In health, emotions are integrated with autonomic bodily responses. Emotional stimuli elicit changes in somatic (including autonomic) bodily states, which feedback to influence the expression of emotional feelings. In patients with spinal cord injury (SCI), this integration of emotion and bodily arousal is partially disrupted, impairing both efferent generation of sympathetic responses and afferent sensory feedback of visceral state via the spinal cord. A number of theoretical accounts of emotion predict emotional deficits in SCI patients, particularly at the level of emotional feelings, yet evidence for such a deficit is equivocal. We used functional MRI (fMRI) and a basic emotional learning paradigm to investigate the expression of emotion-related brain activity consequent upon SCI. We scanned seven SCI patients and seven healthy controls during an aversive fear conditioning task. Subjects viewed randomized presentations of four angry faces. One of the faces (CS + arm) was associated with delivery of electrical shock to the upper arm on 50% of trials. This shock was painful to all subjects. A face of the same gender acted as a ‘safe’ control stimulus (CS – arm). In both control subjects and SCI patients, painful cutaneous stimulation of the arm evoked enhanced activity within components of a central pain matrix, including dorsal anterior cingulate, right insula and medial temporal lobe. However, SCI patients differed from controls in conditioning-related brain activity. SCI patients showed a relative enhancement of activity within dorsal anterior cingulate, periaqueductal grey matter (PAG) and superior temporal gyrus. Conversely, SCI patients showed relative attenuation of activity in subgenual cingulate, ventromedial prefrontal and posterior cingulate cortices to threat of painful arm stimulation (CS + arm > CS – arm). Our findings provide evidence for differences in emotion-related brain activity in SCI patients. We suggest that the observed functional abnormalities including enhanced anterior cingulate and PAG reflect central sensitization of the pain matrix, while decreased subgenual cingulate activity may represent a substrate underlying affective vulnerability in SCI patients consequent upon perturbation of autonomic control and afferent visceral representation. Together these observations may account for motivational and affective sequelae of SCI in some individuals.

Objective. Spinal cord injury (SCI) results in disruption of descending tonic activation of sympathetic circuits in the spinal cord. The authors determined whether different stimuli that increase sympathetic activity induced cutaneous vasoconstriction (skin vasomotor reflex, SkVR) above and below the level of lesion in subjects with clinically complete SCI.Methods. Baseline skin blood flow (SkBF) and SkVR reduction rate in the pulp of the finger and great toe was measured by laser Doppler probes in chronic complete SCI and in controls.Results. In the finger, baseline SkBF was similar in SCI and controls. The SkVR was elicited by all stimuli in controls but was significantly diminished to gasp, mental arithmetic, tactile stimulation, cutaneous cold, and deep breathing in high SCI compared to controls. In the toe, baseline SkBF was less stable in both controls and SCI. SkVR trends were identified in controls, and responses were not present or greatly reduced in high and low SCI.Conclusions. Measurements of skin vasomotor reflexes to physiological stimuli may be a noninvasive method to evaluate the extent of sympathetic adrenergic pathways in chronic SCI. This is of clinical relevance in monitoring recovery of sympathetic adrenergic function either spontaneously or following repair interventions.

Human anterior cingulate function has been explained primarily within a cognitive framework. We used functional MRI experiments with simultaneous electrocardiography to examine regional brain activity associated with autonomic cardiovascular control during performance of cognitive and motor tasks. Using indices of heart rate variability, and high- and low-frequency power in the cardiac rhythm, we observed activity in the dorsal anterior cingulate cortex (ACC) related to sympathetic modulation of heart rate that was dissociable from cognitive and motor-related activity. The findings predict that during effortful cognitive and motor behaviour the dorsal ACC supports the generation of associated autonomic states of cardiovascular arousal. We subsequently tested this prediction by studying three patients with focal damage involving the ACC while they performed effortful cognitive and motor tests. Each showed abnormalities in autonomic cardiovascular responses with blunted autonomic arousal to mental stress when compared with 147 normal subjects tested in identical fashion. Thus, converging neuroimaging and clinical findings suggest that ACC function mediates context-driven modulation of bodily arousal states.

A fundamental human expectation is to stand upright. This exposes the cardiovascular system to gravitational forces, with a fall in pressure above heart level exposing organs such as the brain to impaired perfusion if adequate adaptive mechanisms are not activated. The autonomic nervous system plays an important role in the initial response to standing upright, and can be affected by several disorders, some rare, some common. Autonomic failure can result in orthostatic hypotension with hypoperfusion of vital organs, causing a variety of symptoms including syncope. Thus, it is important to recognise orthostatic hypotension, determine its aetiology, evaluate and treat it. Intermittent autonomic dysfunction (such as neurally mediated syncope without chronic neurogenic failure) also results in falls and syncope; various forms include the ‘common faint' (vasovagal syncope) and carotid sinus hypersensitivity (especially in the elderly). Orthostatic intolerance without orthostatic hypotension is increasingly recognised as due to an autonomic disturbance. New techniques are helping to unravel the functional anatomy of cerebral autonomic centres and their pathways in the causation of orthostatic intolerance.

Hypothalamic dopaminergic pathways are involved in the regulation of growth hormone and prolactin release from the anterior pituitary. Neuroendocrine studies in patients with multiple system atrophy (MSA), in whom there is a reported loss of hypothalamic dopamine, are few and contradictory. We therefore studied the neuroendocrine responses to 250 mg levodopa (plus 25 mg carbidopa) in subjects with MSA (n = 15), and compared them with age‐ and sex‐matched healthy control subjects (n = 8). There were no significant differences in basal or post‐levodopa levels of growth hormone (GH), growth hormone‐releasing hormone (GHRH), glucose, insulin‐like growth factor (IGF‐1), or thyroid‐stimulating hormone (TSH) between the groups. In patients with MSA, basal levels of prolactin were elevated (21.1 ± 5.2 ng/mL [mean ± standard error]) compared with control subjects (12.1 ± 1.7, p <0.05), and after l‐dopa there was increased variability in prolactin response with less suppression compared with control subjects. In conclusion, in patients with MSA, the GHRH and GH responses to l‐dopa were preserved and were similar to responses in age‐matched control subjects. In contrast, there was impaired dopaminergic suppression of prolactin secretion. In patients with MSA this may represent a selective dysfunction, rather than generalized loss, of tubero‐infundibular dopaminergic neurones.

The cardiovascular responses to tracheal suction were observed in 4 consecutive recently-injured tetraplegics with physiologically complete cervical spinal cord transections (C 3–5) who were in spinal shock and needed artificial ventilation. In all 4 patients tracheal suction induced bradycardia and in 2 patients even cardiac arrest. The bradycardia occurred when the patients were hypoxic, and was prevented by the addition of oxygen to inspired air, or, if this was inadequate, by the administration of atropine. Two of the patients were again studied several months later, after return of isolated spinal cord activity and spontaneous breathing. In both patients tracheal suction then caused tachycardia and increased respiratory effort.

1. In human sympathetic denervation due to primary autonomic failure, food and exercise in combination may produce a cumulative blood pressure lowering effect due to simultaneous splanchnic and skeletal muscle dilatation unopposed by corrective cardiovascular reflexes. We studied 12 patients with autonomic failure during and after 9 min of supine exercise, when fasted and after a liquid meal. Standing blood pressure was also measured before and after exercise. 2. When fasted, blood pressure fell during exercise from 162 ± 7/92 ± 4 to 129 ± 9/70 ± 5 mmHg (mean arterial pressure by 22 ± 5%), P < 0.0005. After the meal, blood pressure fell from 159 ± 8/88 ± 6 to 129 ± 6/70 ± 4 mmHg (mean arterial pressure by 22 ± 3%), P < 0.0001, and further during exercise to 123 ± 6/61 ± 3 mmHg (mean arterial pressure by 9 ± 3%), P < 0.01. The stroke distance—heart rate product, an index of cardiac output, did not change after the meal. During exercise, changes in the stroke distance—heart rate product were greater when fasted. 3. Resting forearm and calf vascular resistance were higher when fasted. Calf vascular resistance fell further after exercise when fasted. Resting superior mesenteric artery vascular resistance was lower when fed; 0.19 ± 0.02 compared with 032 ± 0.06, P < 0.05. After exercise, superior mesenteric artery vascular resistance had risen by 82%, to 0.53 ± 0.12, P < 0.05 (fasted) and by 47%, to 0.29 ± 0.05, P < 0.05 (fed). 4. On standing, absolute levels of blood pressure were higher when fasted [83 ± 7/52 ± 7 compared with 71 ± 2/41 ± 3 (fed), each P < 0.05]. Subjects were more symptomatic on standing post-exercise when fed. 5. In human sympathetic denervation, exercise in the fed state lowered blood pressure further than when fasted and worsened symptoms of postural hypotension.

To investigate the effects of the somatostatin analogue octreotide, which inhibits the release of various peptides, on 24-h ambulatory blood pressure profiles in subjects with primary (idiopathic) autonomic failure due to sympathetic denervation, and in particular to determine whether octreotide reduces daytime hypotension and whether it causes or accentuates nocturnal hypertension.

The contribution of neurogenic mechanisms in maintaining hypertension was investigated in 13 patients with unilateral renal artery stenosis (twelve with normal, one with grossly elevated plasma renin levels) by determining the haemodynamic and hormonal responses to the centrally acting sympatholytic agent, clonidine. The same patients were studied after captopril to determine the dependency of their blood pressure on the direct peripheral effects of angiotensin-II. Sixteen patients with essential hypertension (normal plasma renin) were additionally studied after clonidine. After clonidine, blood pressure fell markedly in patients with renal artery stenosis (17 ± 3%) and essential hypertension (18 ± 2%). In both groups, clonidine lowered cardiac output by a reduction in stroke volume and heart rate; forearm vascular resistance was unchanged but digital skin vascular resistance fell. Plasma noradrenaline levels were normal in both groups and fell after clonidine; plasma renin activity and aldosterone levels were unchanged. After captopril, blood pressure fell minimally (5 ± 3%) in renal artery stenosis patients; cardiac output fell and forearm and digital skin vascular resistance were unchanged. Plasma renin activity rose, plasma aldosterone fell and plasma noradrenaline was unchanged after captopril. In the patient with grossly elevated renin levels, blood pressure fell minimally (6%) after clonidine, but unlike others fell profoundly (37%) after captopril. We conclude that, in the majority of our renal artery stenosis patients, despite the elevated blood pressure, sympathetic nervous activity was not reduced. Central neurogenic mechanisms appear to play an important role in maintaining raised blood pressure. In the same patients the peripheral effects of angiotensin-II did not maintain vascular tone or hypertension. The ischaemic kidney has a key role however, as revascularization or nephrectomy cured or ameliorated the hypertension.

The effects of the somatostatin analogue, octreotide on postural hypotension have been compared with placebo, before and after food ingestion in two groups with primary autonomic failure; patients with pure autonomic failure, and patients with additional neurological involvement as part of multiple system atrophy. After placebo, supine blood pressure was unchanged, but after octreotide, it rose in both groups. Octreotide reduced pre-prandial postural and supine post-prandial hypotension in both pure autonomic failure and multiple system atrophy patients. Postural hypotension post-prandially was considerably worse after placebo; this was reduced after octreotide. Plasma noradrenaline and adrenaline levels remained unchanged. Plasma glucose levels rose higher and faster after placebo. Insulin levels were similar in both groups at rest, but rose higher in patients with pure autonomic failure after placebo, After octreotide, the insulin response in both groups was suppressed. We conclude that octreotide prevents post-prandial hypotension in both groups with primary autonomic failure and additionally reduces postural hypotension both before and after food ingestion. The greater rise in insulin levels in patients with pure autonomic failure suggests that insulin may be a contributing factor to the more severe post-prandial hypotension observed in this group of patients.

2Blood pressure, superior mesenteric artery (SMA) and skeletal muscle blood flow, cardiac index (CI) and systemic vascular resistance responses to supine leg exercise were measured in six age‐matched normal subjects (controls) and in eleven subjects with sympathetic denervation due to primary autonomic failure (AF).2During exercise, blood pressure rose in controls but fell markedly in AF. After exercise, blood pressure rapidly returned to baseline in controls but remained low in AF. During exercise, systemic vascular resistance fell in controls and AF but tended to fall further in AF and remained low post exercise. CI increased similarly in controls and AF.3During exercise, SMA blood flow fell similarly in controls and AF, but the fall initially was slower in AF; recovery was more rapid post exercise in controls. SMA vascular resistance tended to rise less and more slowly in AF and remained elevated post exercise.4Forearm muscle (FM) blood flow and FM vascular resistance did not change from resting values in controls or AF post exercise. After exercise, leg muscle (LM) blood flow rose and LM vascular resistance fell equally in both groups although LM blood flow remained elevated, 10 min post exercise in AF.5In sympathetically denervated humans, increased blood flow (due to excessive vasodilatation, lack of sympathetic restraint, or both) in leg muscle during and after exercise in combination with impaired splanchnic vasoconstriction in the early stages of exercise may have contributed to exercise‐induced hypotension.

Abnormal postprandial cardiovascular responses such as postprandial hypotension (PPH) occur in primary autonomic failure and contribute significantly to morbidity. The extent and frequency of PPH and its relationship to the parkinsonian state in idiopathic Parkinson's disease (IPD) is unknown. By studying 20 patients with IPD (without autonomic failure) and 16 age‐matched controls after both groups ingested a standard isocaloric balanced liquid meal we have shown that supine PPH complicates IPD and is reduced to marked worsening of the parkinsonian state as measured by a cumulative score of tremor, rigidity, bradykinesia, posture, and gait, Furthermore, significant postural hypotension is unmasked that results in posturnal intolerance due to presyncopal symptoms. Our study in posturnal intolerance due to presyncopal symptoms. Our study indicates that, in patients with IPD, ingestion of a meal may lead to abnormal postprandial cardiovascular responsea and aggravation of the parkinsonian state. The underlying mechanisms are unclear, although vasodilatory gut peptides released in response to food ingestion may be contributory.

1. In conscious rabbits, intravenous morphine caused hypertension, bradycardia, hyperglycaemia and increased plasma adrenaline and noradrenaline. These effects were prevented by ganglionic blockade with pentolinium. 2. The cardiovascular responses to morphine were not altered by pretreatment with a vasopressin V1-receptor antagonist. 3. After bilateral adrenalectomy morphine caused a similar rise in noradrenaline but no increase in adrenaline. The rise in blood pressure was attenuated and the hyperglycaemia was abolished. 4. Adrenaline infused intravenously to mimic the levels that occurred after morphine caused a similar degree of hyperglycaemia but only a small increase in blood pressure. 5. Pretreatment with intracerebroventricular naloxone prevented the morphine-induced hypertension, hyperglycaemia, increase in plasma catecholamines, respiratory depression and sedation. 6. These results demonstrate that, in conscious rabbits, intravenous morphine causes hypertension by increasing sympathetic vasoconstrictor nerve activity and elevating plasma adrenaline levels; the latter alone produces the hyperglycaemia. Vasopressin release is not involved in the hypertensive response to morphine. The effects of morphine appear to result from stimulation of central opiate receptors leading to enhanced sympathoadrenal outflow.

1. In conscious rabbits, intravenous morphine (3 mg/kg) caused hypertension, bradycardia, hyperglycaemia and sedation. These changes were accompanied by large increases in plasma adrenaline and smaller increases in plasma noradrenaline. 2. These effects of morphine were prevented by intravenous naloxone, demonstrating their dependence on stimulation of opiate receptors. 3. Pretreatment with the antihistamines cimetidine and chlorpheniramine enhanced the morphine-induced rise in blood pressure, excluding a role for histamine release in the hypertensive action of morphine. 4. The centrally acting α2-adrenergic agonist clonidine prevented the morphine-induced hypertension and rise in plasma catecholamines, suggesting that these effects are exerted via central pathways. Clonidine alone reduced blood pressure and heart rate and produced hyperglycaemia. 5. α-Adrenergic blockade with phenoxybenzamine reduced the increase in blood pressure after morphine, although the increase in plasma catecholamines was augmented. 6. Pentobarbitone anaesthesia prevented the morphine-induced cardiovascular changes, the increase in plasma catecholamines and the hyperglycaemia. 7. These findings indicate, that in conscious rabbits, morphine induces hypertension by stimulation of opiate receptors leading to increased sympatho-adrenal activity. The hyperglycaemia appears to be in response to secretion of adrenaline. These effects probably result from a central action of morphine.

β-Adrenergic receptor blockers are one of a number of therapeutic agents promoted as having beneficial effects in vasovagal syncope. In this issue of Clinical Science, Eldadah and co-workers have investigated the effect of the β-adrenergic receptor blocker propranolol in preventing syncope in a double-blind cross-over trial in eight subjects with a diagnosis based on tilt table testing and elevated plasma adrenaline levels during syncope. Of these, seven did not respond and the authors therefore suggest that this drug has no role in the management of vasovagal syncope. Their laboratory-based study, however, raises a number of issues regarding terminology, choice of subjects, the value and role of investigations directed towards diagnosis and in understanding pathophysiological mechanisms, and the relevance of such trials to individual subjects with vasovagal syncope.

OBJECTIVE To report a case of a disturbance of taste and smell associated with the α-adrenoceptor agonist midodrine.CASE SUMMARY A 64-year-old white man with autonomic failure was started on midodrine 5 mg/day as treatment for orthostatic hypotension. After 3 months, the dose was increased to 12.5 mg/day, whereupon he noted a new onset of taste and smell disturbance. These symptoms made eating so unpleasant that the man greatly reduced his food intake, leading to significant weight loss. In addition, he experienced well-recognized adverse effects of midodrine, such as scalp pruritus, after the dose increase. All symptoms resolved with a dose reduction of midodrine (to 5 mg/day), and the patient increased his food intake, resulting in a return to his initial body weight.DISCUSSION Midodrine is commonly associated with dose-dependent adverse effects, such as scalp pruritus and cutis anserina. Disorders of taste and smell have not been previously reported with midodrine, although it has been suggested that other sympathomimetic drugs may have effects on the olfactory threshold. Severe disorders of taste and smell may impact not only on a patient's quality of life, but also on their physical well-being, with significant weight loss being reported in this case. According to the Naranjo probability scale, this patient's taste and smell disturbance was probably associated with midodrine.CONCLUSIONS The use of midodrine may be associated with taste and smell disturbance. This case suggests that such an association is likely to be dose dependent.

A patient with recurrent episodes of dizziness and blackouts is described. Detailed cardiac and neurological investigations were normal. Autonomic assessment excluded postural hypotension and confirmed normal sympathetic vasoconstrictor function. Cardiac parasympathetic function in response to deep breathing, hyperventilation and ocular pressure was normal. Left carotid sinus massage only reproducibly lowered blood pressure with minimal change in heart rate. This occurred mainly during head-up tilt. The fall in blood pressure was not affected by the muscarinic blocker atropine, or the peptide release inhibitor, octreotide. A diagnosis of left carotid sinus hypersensitivity of the vasodepressor variety was made. Left carotid sinus denervation was performed. This successfully prevented further episodes of dizziness and blackouts. The ability to measure beat-to-beat blood pressure non-invasively was of particular importance in diagnosis, and in the assessment of management options in this patient.

The role of central pressor mechanisms in the maintenance of blood pressure in six hypertensive patients with angiographically proven unilateral renal artery stenosis was investigated by studying the haemodynamic and hormonal responses before and after central sympathetic blockade with clonidine. To assess the dependency of blood pressure on the direct effects of angiotensin II, the same patients were studied on a separate occasion after administration of the angiotensin converting enzyme (ACE) inhibitor, captopril. There was a substantial fall in blood pressure after administration of clonidine with a smaller fall after captopril. Clonidine-induced hypotension was accompanied by a fall in cardiac output, through a reduction in the stroke volume and heart rate. Forearm vascular resistance was unchanged. There was a selective decrease in digital skin vascular resistance and plasma noradrenaline, indicating reduced sympathetic activity. Plasma renin activity and aldosterone levels did not fall. After administration of captopril, there was a fall in cardic output due to a fall in the stroke volume but not in the heart rate. Forearm vascular resistance, digital skin vascular resistance and plasma noradrenaline were unchanged. Plasma renin activity rose and plasma aldosterone fell.