Biomedical subjects

David Robertson

Publications and source records attributed to David Robertson.

At least 73 records · Page 4Linked to original sources

PubMed2003

Genetic basis of autonomic dysfunction.

The human genome has become a roadmap for elucidation of the pathophysiology of disease. It is likely that mutations in more than 1000 of the approximately 30,000 human genes will lead to autonomic abnormalities, either directly or indirectly. This review highlights some of these, which exert major effects on catecholamine metabolism and relate specific catecholaminergic phenotypes to neurogenetic disorders. Distinctive catecholamine patterns in several neurogenetic conditions may reflect direct or indirect effects of gene mutations. These neurochemical patterns can provide potentially important clues to the diagnosis, treatment, and pathophysiology of neurogenetic disorders.

Animals↗

PubMed2003

Ureteral tissue balloon expansion for laparoscopic bladder augmentation: survival study.

BACKGROUND AND PURPOSE: The search for the perfect urinary bladder substitute continues. Despite their inherent limitations, intestinal segments remain the commonest material for bladder reconstruction. The ureter, with its transitional epithelium, may be the ideal tissue to augment the bladder. Ikeguchi et al reported the feasibility of chronic ureteral balloon expansion by open surgery (J Urol 1998;159:1665). Herein, we propose a completely minimally invasive approach to balloon overdilate a segment of juxtavesical ureter incrementally and to use this in-line tissue-expanded ureteral patch to augment the bladder laparoscopically. MATERIALS AND METHODS: In five female pigs, a novel ureteral expansion balloon device (Microvasive, MA) was inserted percutaneously and advanced antegrade into the juxtavesical ureter. The device has two channels: one for balloon inflation and the other for draining the kidney. After progressive ureteral expansion over a 3- to 4-week period, laparoscopic augmentation ureterocystoplasty was performed. Animals were euthanized at 15 days (N = 1), 1 month (N = 1), 2 months (N = 1), and 3 months (N = 2). RESULTS: Percutaneous balloon device placement was technically successful in all five cases (mean operating room time 52 minutes). The mean volume of the tissue-expanded ureter at 1, 2, and 3 weeks was 12.9 cc, 60.3 cc, and 171.8 cc, respectively. Laparoscopic augmentation ureterocystoplasty with (N = 3) or without (N = 2) concomitant subtotal cystectomy was technically successful in all five cases without any open conversion. The mean operative time was 126.5 minutes, and the mean blood loss was 29 mL. Postoperative complications consisted of one case each of pyelonephritis and ureteral stricture. At autopsy, the mean capacity of the bladder was 574 mL, and the P(ves) at maximum capacity was 14 cm H(2)O. Histologic examination of the tissue-expanded ureter revealed regenerated transitional epithelium and muscle hypertrophy. CONCLUSIONS: Chronic ureteral tissue expansion can be carried out safely and efficaciously. The expanded tissue is thick, healthy, and vascular, with histologic features of normal transitional epithelium and muscle hypertrophy and hyperplasia. This expanded ureteral tissue can be used to augment the bladder with laparoscopic techniques. Such augmented bladders do not show significant shrinkage and possess urodynamic characteristic of normal capacity and normal compliance over a follow-up of 3 months.

Anastomosis, Surgical↗

PubMed2003

The sympathetic nervous system in hypertension: assessment by blood pressure variability and ganglionic blockade.

OBJECTIVE: To determine if the contribution of the sympathetic nervous system to blood pressure could be evidenced by low-frequency oscillations of systolic blood pressure (LF(SBP)), reflecting vascular sympathetic modulation, or by the decrease in blood pressure after autonomic blockade. DESIGN: We studied multiple system atrophy (MSA) patients, in whom supine hypertension is maintained by residual sympathetic tone ('positive controls'); pure autonomic failure (PAF) patients, in whom supine hypertension is largely independent of sympathetic tone ('negative controls'); essential hypertensive patients (HTN) and normotensive subjects (NTN). RESULTS: Supine systolic blood pressure (SBP) was 204 +/- 8, 185 +/- 6, 177 +/- 9 and 130 +/- 4 mmHg in MSA, PAF, HTN and NTN, respectively. LF(SBP) was higher in MSA and HTN (5.7 +/- 1.5 and 5.8 +/- 1.4 mmHg(2) compared to NTN and PAF (3.3 +/- 0.5 and 1.1 +/- 0.5 mmHg(2). Trimethaphan 2-4 mg/min induced complete autonomic blockade and lowered SBP below 125 mmHg in all NTN and all but one MSA (to 111 +/- 3 and 97 +/- 9 mmHg). SBP remained elevated in PAF (164 +/- 7 mmHg). Responses in HTN were variable; SBP decreased below 125 mmHg in three and remained elevated in four patients. The decrease in LF(SBP) correlated with the reduction in SBP, with a steeper slope in MSA and HTN compared to NTN (29.0 +/- 5.5, 8.4 +/- 1.6 and 3.6 +/- 1.2 mmHg/mmH (2), respectively). CONCLUSION: Ganglionic blockade, alone or coupled to LF(SBP), discriminated between human models of sympathetic-dependent (MSA) and independent (PAF) hypertension. This approach may aid in assessing the contribution of the sympathetic nervous system in essential hypertension, in which sympathetic dependence is variably expressed.

Aged↗

PubMed2002

Dysautonomias: clinical disorders of the autonomic nervous system.

The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after "patchy" autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with beta-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.

Autonomic Nervous System↗

PubMed2002

Modulation of QT interval during autonomic nervous system blockade in humans.

BACKGROUND: It is thought that the autonomic nervous system modulates QT interval, but traditional autonomic blockade combining propranolol and atropine has produced conflicting results. We used the alternative approach of interrupting neurotransmission at the level of autonomic ganglia to determine its effect on the QT interval. METHODS AND RESULTS: We infused trimethaphan at increasing doses (0.5 to 10 mg/min IV) while monitoring heart rate, heart rate variability spectra, QT interval, and blood pressure in 10 normal volunteers, 9 patients with multiple system atrophy (MSA), and 8 patients with pure autonomic failure (PAF). The QT interval was corrected for heart rate using Bazett's formula (QTc). Patients with PAF had very low heart rate variability and a prolonged QTc at baseline (465+/-8 ms) compared with patients with MSA (448+/-6 ms) and normal subjects (432+/-6 ms). In normal subjects, trimethaphan dose-dependently prolonged QTc (to 469+/-7 ms), decreased RR interval (995+/-45 to 670+/-35 ms), and abolished heart rate variability. In MSA patients, trimethaphan also prolonged QTc (to 463+/-7 ms) and reduced heart rate variability but did not significantly change RR interval (from 813+/-38 to 801+/-39). CONCLUSIONS: Autonomic blockade prolongs QT interval in normal subjects to a similar duration as in PAF patients. Furthermore, blocking residual autonomic tone in PAF patients is associated with a further increase in QT interval length. Patients with MSA have greater residual sympathetic tone and greater prolongation of the QT interval during ganglionic blockade than PAF patients.

Aged↗

PubMed2002

Cardiovascular and sympathetic neural responses to handgrip and cold pressor stimuli in humans before, during and after spaceflight.

Astronauts returning to Earth have reduced orthostatic tolerance and exercise capacity. Alterations in autonomic nervous system and neuromuscular function after spaceflight might contribute to this problem. In this study, we tested the hypothesis that exposure to microgravity impairs autonomic neural control of sympathetic outflow in response to peripheral afferent stimulation produced by handgrip and a cold pressor test in humans. We studied five astronauts approximately 72 and 23 days before, and on landing day after the 16 day Neurolab (STS-90) space shuttle mission, and four of the astronauts during flight (day 12 or 13). Heart rate, arterial pressure and peroneal muscle sympathetic nerve activity (MSNA) were recorded before and during static handgrip sustained to fatigue at 40 % of maximum voluntary contraction, followed by 2 min of circulatory arrest pre-, in- and post-flight. The cold pressor test was applied only before (five astronauts) and during flight (day 12 or 13, four astronauts). Mean (+/- S.E.M.) baseline heart rates and arterial pressures were similar among pre-, in- and post-flight measurements. At the same relative fatiguing force, the peak systolic pressure and mean arterial pressure during static handgrip were not different before, during and after spaceflight. The peak diastolic pressure tended to be higher post- than pre-flight (112 +/- 6 vs. 99 +/- 5 mmHg, P = 0.088). Contraction-induced rises in heart rate were similar pre-, in- and post-flight. MSNA was higher post-flight in all subjects before static handgrip (26 +/- 4 post- vs. 15 +/- 4 bursts min(-1) pre-flight, P = 0.017). Contraction-evoked peak MSNA responses were not different before, during, and after spaceflight (41 +/- 4, 38 +/- 5 and 46 +/- 6 bursts min(-1), all P > 0.05). MSNA during post-handgrip circulatory arrest was higher post- than pre- or in-flight (41 +/- 1 vs. 33 +/- 3 and 30 +/- 5 bursts min(-1), P = 0.038 and 0.036). Similarly, responses of MSNA and blood pressure to the cold pressor test were well maintained in-flight. We conclude that modulation of muscle sympathetic neural outflow by muscle metaboreceptors and skin nociceptors is preserved during short duration spaceflight.

Adult↗

PubMed2002

Autonomic control after blockade of the norepinephrine transporter: a model of orthostatic intolerance.

Orthostatic intolerance is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine (NE) transporter (NET) has been implicated in a genetic form of the disorder. We assessed the combined central and peripheral effects of pharmacological NET blockade on cardiovascular regulation and baroreflex sensitivity in rats. NE reuptake was blocked chronically in female Sprague-Dawley rats by the NET antagonist desipramine (DMI). Treated animals demonstrated an elevated supine heart rate, reduced tyramine responsiveness, and a reduced plasma ratio of the intraneuronal NE metabolite dihydroxyphenylglycol relative to NE, all of which are consistent with observations in human NET deficiency. Spectral analysis revealed a dramatic decrease in low-frequency spectral power after DMI that was consistent with decreased sympathetic outflow. Stimulation of the baroreflex with the vasodilator nitroprusside revealed an attenuated tachycardia in DMI-treated animals. This indicated that the DMI-induced sympathoinhibitory effects of increased NE in the brain stem predominates over the functional elevation of NE stimulation of peripheral targets. Thus attenuated baroreflex function and reduced sympathetic outflow may contribute to the orthostatic intolerance of severe NET deficiency.

Adrenergic Uptake Inhibitors↗

PubMed2002

The nature of the autonomic dysfunction in multiple system atrophy.

The concept that multiple system atrophy (MSA, Shy-Drager syndrome) is a disorder of the autonomic nervous system is several decades old. While there has been renewed interest in the movement disorder associated with MSA, two recent consensus statements confirm the centrality of the autonomic disorder to the diagnosis. Here, we reexamine the autonomic pathophysiology in MSA. Whereas MSA is often thought of as "autonomic failure", new evidence indicates substantial persistence of functioning sympathetic and parasympathetic nerves even in clinically advanced disease. These findings help explain some of the previously poorly understood features of MSA. Recognition that MSA entails persistent, constitutive autonomic tone requires a significant revision of our concepts of its diagnosis and therapy. We will review recent evidence bearing on autonomic tone in MSA and discuss their therapeutic implications, particularly in terms of the possible development of a bionic baroreflex for better control of blood pressure.

Adrenergic Fibers↗

PubMed2002

Four faces of baroreflex failure: hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia.

BACKGROUND: The baroreflex normally serves to buffer blood pressure against excessive rise or fall. Baroreflex failure occurs when afferent baroreceptive nerves or their central connections become impaired. In baroreflex failure, there is loss of buffering ability, and wide excursions of pressure and heart rate occur. Such excursions may derive from endogenous factors such as stress or drowsiness, which result in quite high and quite low pressures, respectively. They may also derive from exogenous factors such as drugs or environmental influences. METHODS AND RESULTS: Impairment of the baroreflex may produce an unusually broad spectrum of clinical presentations; with acute baroreflex failure, a hypertensive crisis is the most common presentation. Over succeeding days to weeks, or in the absence of an acute event, volatile hypertension with periods of hypotension occurs and may continue for many years, usually with some attenuation of pressor surges and greater prominence of depressor valleys during long-term follow-up. With incomplete loss of baroreflex afferents, a mild syndrome of orthostatic tachycardia or orthostatic intolerance may appear. Finally, if the baroreflex failure occurs without concomitant destruction of the parasympathetic efferent vagal fibers, a resting state may lead to malignant vagotonia with severe bradycardia and hypotension and episodes of sinus arrest. CONCLUSIONS: Although baroreflex failure is not the most common cause of the above conditions, correct differentiation from other cardiovascular disorders is important, because therapy of baroreflex failure requires specific strategies, which may lead to successful control.

Autonomic Nervous System Diseases↗

PubMed2002

Water drinking as a treatment for orthostatic syndromes.

PURPOSE: Water drinking increases blood pressure in a substantial proportion of patients who have severe orthostatic hypotension due to autonomic failure. We tested the hypothesis that water drinking can be used as a practical treatment for patients with orthostatic and postprandial hypotension, as well as those with orthostatic tachycardia. SUBJECTS AND METHODS: We studied the effect of drinking water on seated and standing blood pressure and heart rate in 11 patients who had severe orthostatic hypotension due to autonomic failure and in 9 patients who had orthostatic tachycardia due to idiopathic orthostatic intolerance. We also tested the effect of water drinking on postprandial hypotension in 7 patients who had autonomic failure. Patients drank 480 mL of tap water at room temperature in less than 5 minutes. RESULTS: In patients with autonomic failure, mean (+/- SD) blood pressure after 1 minute of standing was 83 +/- 6/53 +/- 3.4 mm Hg at baseline, which increased to 114 +/- 30/66 +/- 18 mm Hg (P <0.01) 35 minutes after drinking. After a meal, blood pressure decreased by 43 +/- 36/20 +/- 13 mm Hg without water drinking, compared with 22 +/- 10/12 +/- 5 mm Hg with drinking (P <0.001). In patients with idiopathic orthostatic intolerance, water drinking attenuated orthostatic tachycardia (123 +/- 23 beats per minute) at baseline to 108 +/- 21 beats per minute after water drinking ( P <0.001). CONCLUSION: Water drinking elicits a rapid pressor response in patients with autonomic failure and can be used to treat orthostatic and postprandial hypotension. Water drinking moderately reduces orthostatic tachycardia in patients with idiopathic orthostatic intolerance. Thus, water drinking may serve as an adjunctive treatment in patients with impaired orthostatic tolerance.

Adult↗

PubMed2002

Baroreflex buffering and susceptibility to vasoactive drugs.

BACKGROUND: The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known. METHODS AND RESULTS: We characterized baroreflex function and responses to vasoactive drugs in patients with idiopathic orthostatic intolerance, patients with essential hypertension, patients with monogenic hypertension and brachydactyly, patients with multiple system atrophy, and control subjects. We used phenylephrine sensitivity during ganglionic blockade as a measure of baroreflex buffering. Phenylephrine (25 microg) increased systolic blood pressure 6+/-1.6 mm Hg in control subjects, 6+/-1.1 mm Hg in orthostatic intolerance patients, 18+/-3.9 mm Hg in patients with essential hypertension, 31+/-3.4 mm Hg in patients with monogenic hypertension, and 25+/-3.4 mm Hg in patients with multiple system atrophy. Similar differences in sensitivities between groups were observed with nitroprusside. The sensitivity to vasoactive drugs was highly correlated with baroreflex buffering function and to a lesser degree with baroreflex control of heart rate. In control subjects, sensitivities to nitroprusside and phenylephrine infusions were correlated with baroreflex heart rate control and sympathetic nerve traffic. CONCLUSIONS: Our findings are consistent with an important effect of baroreflex blood pressure buffering on the sensitivity to vasoactive drugs. They suggest that even moderate changes in baroreflex function may have a substantial effect on the sensitivity to vasoactive medications.

Adrenergic beta-Agonists↗

PubMed2002

Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency.

Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH.

Animals↗

PubMed2002

Influence of microgravity on astronauts' sympathetic and vagal responses to Valsalva's manoeuvre.

When astronauts return to Earth and stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied brief autonomic and haemodynamic transients provoked by graded Valsalva manoeuvres in astronauts on Earth and in space, and tested the hypothesis that exposure to microgravity impairs sympathetic as well as vagal baroreflex responses. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, respiration and peroneal nerve muscle sympathetic activity in four healthy male astronauts (aged 38-44 years) before, during and after the 16 day Neurolab space shuttle mission. Astronauts performed two 15 s Valsalva manoeuvres at each pressure, 15 and 30 mmHg, in random order. Although no astronaut experienced presyncope after the mission, microgravity provoked major changes. For example, the average systolic pressure reduction during 30 mmHg straining was 27 mmHg pre-flight and 49 mmHg in flight. Increases in muscle sympathetic nerve activity during straining were also much greater in space than on Earth. For example, mean normalized sympathetic activity increased 445% during 30 mmHg straining on earth and 792% in space. However, sympathetic baroreflex gain, taken as the integrated sympathetic response divided by the maximum diastolic pressure reduction during straining, was the same in space and on Earth. In contrast, vagal baroreflex gain, particularly during arterial pressure reductions, was diminished in space. This and earlier research suggest that exposure of healthy humans to microgravity augments arterial pressure and sympathetic responses to Valsalva straining and differentially reduces vagal, but not sympathetic baroreflex gain.

Adult↗

PubMed2002

Human muscle sympathetic nerve activity and plasma noradrenaline kinetics in space.

Astronauts returning from space have reduced red blood cell masses, hypovolaemia and orthostatic intolerance, marked by greater cardio-acceleration during standing than before spaceflight, and in some, orthostatic hypotension and presyncope. Adaptation of the sympathetic nervous system occurring during spaceflight may be responsible for these postflight alterations. We tested the hypotheses that exposure to microgravity reduces sympathetic neural outflow and impairs sympathetic neural responses to orthostatic stress. We measured heart rate, photoplethysmographic finger arterial pressure, peroneal nerve muscle sympathetic activity and plasma noradrenaline spillover and clearance, in male astronauts before, during (flight day 12 or 13) and after the 16 day Neurolab space shuttle mission. Measurements were made during supine rest and orthostatic stress, as simulated on Earth and in space by 7 min periods of 15 and 30 mmHg lower body suction. Mean (+/- S.E.M.) heart rates before lower body suction were similar pre-flight and in flight. Heart rate responses to -30 mmHg were greater in flight (from 56 +/- 4 to 72 +/- 4 beats min(-1)) than pre-flight (from 56 +/- 4 at rest to 62 +/- 4 beats min(-1), P < 0.05). Noradrenaline spillover and clearance were increased from pre-flight levels during baseline periods and during lower body suction, both in flight (n = 3) and on post-flight days 1 or 2 (n = 5, P < 0.05). In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33 %) in the same three subjects in whom noradrenaline spillover and clearance were increased. The sympathetic response to 30 mmHg lower body suction was at pre-flight levels or higher in each subject (35 pre-flight vs. 40 bursts min(-1) in flight). No astronaut experienced presyncope during lower body suction in space (or during upright tilt following the Neurolab mission). We conclude that in space, baseline sympathetic neural outflow is increased moderately and sympathetic responses to lower body suction are exaggerated. Therefore, notwithstanding hypovolaemia, astronauts respond normally to simulated orthostatic stress and are able to maintain their arterial pressures at normal levels.

Adult↗

PubMed2002

No increased herniation of the cerebellar tonsils in a group of patients with orthostatic intolerance.

Orthostatic intolerance, seen predominantly in young women, is characterized by symptoms of lightheadedness, fatigue and palpitations in the upright posture. With standing, plasma norepinephrine levels rise dramatically and heart rate often increases by more than 30 beats per minute, although blood pressure does not usually fall. A theory recently popularized in the media suggests that some cases of orthostatic intolerance are related to hindbrain compression, with or without a Chiari I malformation. As a preliminary investigation of this hypothesis, head or cervical spine MRI scans from 23 females with orthostatic intolerance were reviewed. The cerebellar tonsils averaged 0.3 +/- 1.9 mm below the foramen magnum. These results were compared to measurements from a control group averaging 0.4 +/- 2.6 mm above the foramen magnum (P > 0.05). Tonsillar depression of at least 3 mm occurred in 13 % of both the patient group and the control group. Tonsillar herniation was not found to influence supine or upright blood pressure, heart rate or plasma norepinephrine levels in the patients. We conclude that herniation of the cerebellar tonsils is not a common cause of orthostatic intolerance. However, the single measurement of tonsillar depression might underestimate the number of patients with hindbrain compression.

Adult↗

PubMed2002

The broader view: catecholamine abnormalities.

Norepinephrine (NE), a vital neurotransmitter in both the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) through the oxidation of dopamine (DA) to NE. DBH deficiency is a congenital disorder characterized by severe orthostatic hypotension, ptosis, and retrograde ejaculation. Biochemical features of the syndrome include elevated levels of dopamine, undetectable levels of DBH, undetectable tissue and circulating levels of NE and epinephrine. Molecular genetic analysis studies suggested that DBH deficiency is a Mendelian recessive disorder attributable to heterogenous mutations at the DBH locus. DBH deficiency has been treated effectively with L-threo-3,4-dihydroxyphenylserine (DOPS). DOPS is converted directly to NE through decarboxylation by L-aromatic amino acid decarboxylase (AADC), thereby bypassing DBH. Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, syncope, and postural tachycardia. Biochemical features may include plasma NE concentration that is disproportionately high in relation to sympathetic outflow, decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists. A subset of OI patients has pathophysiologic features that have been associated with a genetic polymorphism. The coding mutation, A457P, occurs in one of the alleles of norepinephrine transporter gene of a proband with OI and her family. Alpha-methyl dopa, beta blockers and clonidine, a partial agonist of alpha2-adrenoceptor that acts centrally to reduce sympathetic outflow and lower blood pressure, have been effective in the treatment of this condition. The identification of the genetic polymorphisms involved in the synthesis, transport, storage, and metabolism of the catecholamines may provide new insights into the diagnosis and management of autonomic, cardiovascular, endocrine and psychiatric disorders.

Catecholamines↗

PubMed2002

Genetic basis of clinical catecholamine disorders.

Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.

Catecholamines↗

PubMed2002

Genetic manipulation of noradrenergic neurons.

The neurotransmitter norepinephrine has been the focus of intense investigation for nearly a century. With advances in technology come novel approaches for testing hypotheses about the physiological roles of norepinephrine and the genes involved in norepinephrine (NE) biosynthesis, metabolism, and noradrenergic signaling. Homologous recombination techniques, which generate mice deficient in specific gene products, aid the integrated physiologist and pharmacologist in the evaluation of protein function. Mouse models lacking proteins involved in NE biosynthesis or metabolism provide tools to expand the knowledge previously gleaned from pharmacologic studies. Removal of the biosynthetic enzymes tyrosine hydroxylase and dopamine-beta-hydroxylase yield animals deficient in norepinephrine and have been used to further examine the role of NE in diverse physiologic roles. Complete removal of the vesicular monoamine transporter has demonstrated that mobilizing neurotransmitters to vesicles is required for animal survival. Lastly, the generation of animals in which the ability to remove NE from the synapse is impaired (norepinephrine transporter deficiency and extraneuronal monoamine transporter deficiency) and in which the enzymes responsible for the metabolism of NE have been removed (catechol-O-methyltransferase and monoamine oxidase) has facilitated the study of the long-term physiological consequences of altered NE homeostasis.

Animals↗