Orthostatic intolerance in Behcet's disease.

Neurological manifestations are known to occur in patients with Behcet's Disease (BD) and significantly affect the clinical course of the disease. Nevertheless, the prevalence, pattern and severity of autonomic impairment in such patients have yet to be defined. In this paper, we presented a BD patient with orthostatic tachycardia. Non-invasive standardized autonomic function tests revealed no evidence of autonomic impairment, but profound orthostatic tachycardia accompanied by abnormal catecholamine increase was observed upon standing. The diagnosis of Orthostatic Intolerance (OI) was made and initial symptomatic therapy was started. The contribution of an immunological damage to components of neural pathways in the pathogenesis of the autonomic involvement can be assumed.

Familial orthostatic tachycardia due to norepinephrine transporter deficiency.

UNLABELLED: Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

Multiple system atrophy: new developments in pathophysiology and therapy.

There have been substantial advances in the last five years in understanding the basic and clinical pathophysiology underlying multiple system atrophy (MSA). Identification of glial cytoplasmic inclusions has been the most important organizing principle for further elucidation of underlying mechanisms. Recently, several unexpected developments at the clinical level have been reported. In this article, we will focus on two of these: (1) the recognition that substantial autonomic function is retained in MSA but not modulated appropriately, and (2) a potent pressor effect from ingestion of water, which cannot be explained by currently understood physiologic and pathophysiologic mechanisms. In some patients, water has elicited a 50% increase in blood pressure and been more therapeutically effective than any available pressor drug. By careful coordination of the pressor effect of water and the depressor effect of carbohydrate-rich food, many patients with MSA can now have their blood pressure controlled without pharmacological intervention.

Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat.

The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.

Alteration of cholinergic pressor and antinociceptive responses in rats pretreated with the cholinergic toxin AF64A.

1. In the present study, the pressor and antinociceptive effects of physostigmine and oxotremorine were investigated in rats injected with AF64A intracerebroventricularly. 2. Physostigmine (50-100 micrograms/kg, i.v.)-induced pressor responses were significantly lower in AF64A-injected rats compared with saline-injected animals, whereas oxotremorine (20-80 micrograms/kg, i.v.)-induced responses were found to be similar to those seen in the saline group. 3. The physostigmine (100 micrograms/kg, s.c.)-induced antinociceptive effect was totally abolished by AF64A treatment, but that of oxotremorine (30 micrograms/kg, s.c.) remained unchanged at the tail-flick test. 4. The results of this study present functional evidence for AF64A-produced substantial loss of cholinergic neurons involved in the regulation of blood pressure and nociception but not in postsynaptic muscarinic receptors.

Effect of muscimol on cholinomimetic-induced cardiovascular responses in rats.

Brain acetylcholine and gamma-aminobutyric acid (GABA) are both involved in the regulation of central cardiovascular control. Despite data from anatomical and electrophysiological experiments characterizing the interaction between central GABAergic and cholinergic neurotransmission, the potential significance of this interaction in central cardiovascular regulation remains unknown. The purpose of this study was to determine whether activation of GABA(A) receptors by intracerebroventricular or intrahypothalamic administration of muscimol affects the cholinergic agonist-induced cardiovascular responses. All experiments were performed in conscious, Sprague-Dawley rats instrumented with a guide cannula for drug injection and iliac arterial catheters for direct measurement of mean arterial pressure and heart rate. Administration of a cholinergic agonist, carbachol, either intracerebroventricularly or into the dorsomedial hypothalamic nucleus, produced a significant increase in mean arterial pressure, whereas injection of carbachol into the posterior hypothalamic nucleus caused a slight elevation in blood pressure. Pretreatment with muscimol 10 min before administration of carbachol prevented the carbachol-evoked blood pressure changes. On the other hand, carbachol produced variable changes in heart rate, depending on the site of injection. In [3H]quinuclydinyl benzilate binding experiments, muscimol did not displace the muscarinic radioligand from its binding sites, suggesting that it does not exert any direct antagonistic activity at muscarinic receptors. These results suggest that the dorsomedial hypothalamic nucleus is a potential site of action for microinjected carbachol and that the GABAergic system has an inhibitory influence on cholinergic neurons involved in blood pressure regulation.

Effect of brain acetylcholine depletion on bicuculline-induced cardiovascular and locomotor responses.

Both GABAergic and cholinergic systems are involved in central cardiovascular regulation. Previous studies have shown that GABAA receptor antagonists cause increases in blood pressure, heart rate and locomotor activity. In this study, we examined the role of the depletion of brain acetylcholine on the cardiovascular responses and locomotor activity induced by bicuculline methiodide in conscious Sprague-Dawley rats. The doses of 0.3 and 0.5 nmol of intracerebroventricular bicuculline methiodide produced increases in blood pressure, heart rate and locomotor activity. The dose of 18 nmol of hemicholinium-3 to deplete brain acetylcholine was given intracerebroventricularly one hour prior to bicuculline methiodide. The pressor responses to bicuculline methiodide in animals pretreated with the hemicholinium-3 were higher than those seen in saline-pretreated groups, but locomotor activity and heart rate responses to bicuculline methiodide remained unchanged in hemicholinium-3 pretreatment group. On the other hand, high dose of bicuculline methiodide (0.5 nmol) caused convulsions in some animals pretreated with hemicholinium-3 whereas bicuculline methiodide, alone, did not cause any seizure activity. In conclusion, it seems likely that endogenous brain acetylcholine could be a modulator of GABAA receptor-mediated blood pressure control.

Role of the AV3V region in the pressor responses induced by amygdala stimulation.

The role of the anteroventral third ventricle (AV3V) region in the pressor responses to carbachol injected into the lateral cerebral ventricle (i.c.v.), the electrical stimulation of and carbachol-induced stimulation of, the central nucleus of the amygdala were investigated in conscious, unrestrained Sprague-Dawley rats. I.c.v. and intra-amygdalar carbachol caused a significant rise in blood pressure of 22.9 +/- 2.8 and 16.8 +/- 2.2 mmHg, respectively. Electrical stimulation (1 ms, 80 Hz, 50-300 microA, for 30 s) of the central nucleus of amygdala also produced intensity-dependent pressor effects. Electrolytic lesion of the AV3V region abolished the pressor responses induced by carbachol and by electrical amygdala stimulation. The heart rate changes were also significantly inhibited in the AV3V-lesioned rats. These results indicate that the integrity of the AV3V region is essential for the central cholinergic cardiovascular changes induced by central amygdaloid nucleus stimulation.

The role of brain acetylcholine in GABAA receptor antagonist-induced blood-pressure changes in rat.

Previous experimental studies have shown that intracerebroventricular (i.c.v.) injection of the GABAA receptor antagonist, bicuculline methiodide, results in marked increases in blood pressure due to an increase in sympathetic nervous system activity. It is well recognized that the central cholinergic system is also involved in the regulation of blood pressure. In the present study, we examined the role of brain acetylcholine in the pressor response induced by bicuculline methiodide in conscious Sprague-Dawley rats. I.c.v. (0.05, 0.3 and 0.5 nmol) and intrahypothalamic (40 pmol) administration of bicuculline methiodide produced blood-pressure increases in a dose-dependent manner. Hemicholinium-3 was given i.c.v. 1 h prior to bicuculline methiodide. The depletion of brain acetylcholine was demonstrated by the suppression of physostigmine-induced pressor responses, but blood pressure increases in response to carbachol remained unchanged. The pressor responses to bicuculline methiodide in animals pre-treated with hemicholinium-3 were significantly higher than those seen in saline-pre-treated groups. Likewise, bicuculline methiodide, at a dose that did not alter blood pressure alone, caused pressor responses in rats pre-treated with the nicotinic receptor antagonist, mecamylamine, whereas the muscarinic receptor antagonist, atropine, was ineffective in this respect. In conclusion, it seems likely that endogenous brain acetylcholine has a modulator role on GABAA receptor-mediated blood-pressure control via nicotinic receptors.