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Biomedical subjects

Italo Biaggioni

Publications and source records attributed to Italo Biaggioni.

At least 55 records · Page 3Linked to original sources
PubMed2003

Variations in the dopamine beta-hydroxylase gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy.

Norepinephrine (NE) is the major neurotransmitter of the sympathetic division of the autonomic nervous system (ANS). Recent findings of an association between human NE deficiency and variants at the dopamine beta-hydroxylase (DBH) gene [Kim et al., 2002] prompted us to investigate these markers in patients with autonomic disorders; 38 with orthostatic intolerance (OI), 26 with pure autonomic failure (PAF), and 39 with multiple system atrophy (MSA). Eighty-eight normal controls were included in this study. In contrast to NE deficiency, allele frequency and genotype distribution of the genetic variants showed no differences between autonomic disease patients and controls. In addition, no DBH mutation was found that distinguished autonomic disease patients from controls, suggesting that genetic variants of the DBH gene are not associated with the autonomic diseases OI, PAF, and MSA.

Autonomic Nervous System Diseases↗
PubMed2003

A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells.

Adenosine (Ado) has been suggested to play a role in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. The goal of this study was to determine the effect of Ado and its receptor subtypes on cytokine release by bronchial smooth muscle cells. The A2B Ado receptor (AdoR) was expressed at the highest level among the four AdoR subtypes. Activation of the A2B AdoR by an Ado analog, 5'-(N-ethylcarboxamido)-adenosine (NECA), increased cAMP accumulation with potency (EC50 value) of 21.2 +/- 0.2 microM. The effect of NECA on the expression of the inflammatory cytokines was determined using a cDNA array consisting of 23 cytokine genes and confirmed using real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. NECA increased the release of interleukin-6 and monocyte chemotactic protein-1 proteins with EC50 values of 1.26 +/- 0.25 microM and 0.40 +/- 0.08 microM, respectively, and the maximal folds of induction were 20.8 +/- 1.7- and 6.4 +/- 0.7-fold, respectively. Selective agonists for the A1, A2A, and A3 AdoR subtypes had no effect on cytokine release. The effects of NECA were attenuated by selective antagonists of the A2B AdoR. Thus, Ado increases the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells via activation of the A2B AdoR. Our findings provide a novel mechanism whereby Ado acts as a proinflammatory mediator in the airway.

Adenosine A2 Receptor Antagonists↗
PubMed2003

Neurovascular dissociation with paradoxical forearm vasodilation during systemic tyramine administration.

BACKGROUND: Despite the widespread use of tyramine as a pharmacological tool to assess the effects of norepinephrine release from sympathetic nerve terminals, its vascular effects are not adequately characterized. In particular, previous results indicate that intravenous tyramine produces little if any systemic vasoconstriction, suggesting that tyramine does not cause significant norepinephrine release from sympathetic nerves innervating peripheral vascular beds. To test this hypothesis, we determined the effects of intravenous tyramine on local forearm norepinephrine spillover and vascular resistance. METHODS AND RESULTS: Seven healthy subjects were studied with systemic and local forearm norepinephrine spillover and forearm blood flow at baseline, during systemic tyramine infusion, and after sympathetic stimulation induced by the cold pressor test. Tyramine infusion caused a significant increase in systemic and forearm norepinephrine spillover. The amount of norepinephrine released into the forearm by tyramine was similar to that caused by cold pressor stimulation, 0.15+/-0.05 versus 0.18+/-0.05 ng x dL(-1) x min(-1). As expected, forearm vascular resistance increased during the cold pressor test, but tyramine produced forearm vasodilation (4.5+/-1 versus -5+/-1 mm Hg x dL(-1) x min(-1), P<0.03) despite the increase in local norepinephrine spillover. In 6 additional subjects, plasma dopamine increased significantly during tyramine administration, from 11+/-3 to 662+/-105 pg/mL. CONCLUSIONS: Thus, systemic tyramine infusion evokes a significant increase in peripheral norepinephrine spillover, and this, paradoxically, is associated with local vasodilatation rather than vasoconstriction.

Adult↗
PubMed2003

Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors.

Adenosine is released during tissue injury, ischemia and tumor growth, and promotes angiogenesis. Because mast cells accumulate in the proximity of new blood vessel development, we examined if they may contribute to adenosine-induced angiogenesis. We found that HMC-1 human mast cells express A2A, A2B, and A3 adenosine receptors. The adenosine agonist NECA (100 micromol/L) increased interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and angiopoietin-2 mRNA expression. NECA-induced secretion of IL-8 and VEGF was verified by ELISA. A2B receptors mediate VEGF and IL-8 secretion because neither CGS21680 (selective A2A agonist) nor IB-MECA (selective A3 agonist) produced this effect, and it was inhibited by the selective A2B antagonist IPDX but not by the selective A2A antagonist SCH58261 or the selective A3 antagonist MRS1191. In contrast, the selective A3 agonist IB-MECA (EC50 1 nmol/L) stimulated angiopoietin-2 expression. Conditioned media from NECA-activated HMC-1 stimulated human umbilical vein endothelial cell proliferation and migration, and induced capillary tube formation. Capillary formation induced by mast cell-conditioned media was maximal if both HMC-1 A2B and A3 receptors were activated, whereas activation of A2B receptor alone was less effective. Thus, adenosine A2B and A3 receptors act in a functional cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from human mast cells.

Adenosine↗
PubMed2003

Hereditary dysautonomias: current knowledge and collaborations for the future.

The hereditary dysautonomias (H-Dys) are a large group of disorders that affect the autonomic nervous system. Research in the field of H-Dys is very challenging, because the disorders involve interdisciplinary, integrative, and "mind-body" connections. Recently, medical scientists, NIH/NINDS representatives, and several patient support groups gathered for the first time in order to discuss recent findings and future directions in the H-Dys field. The H-Dys workshop was instrumental in promoting interactions between basic science and clinical investigators. It also allowed attendees to have an opportunity to meet each other, understand the similarities between the various forms of dysautonomia, and experience the unique perspective offered by patients and their families. Future advances in H-Dys research will depend on a novel multi-system approach by investigators from different medical disciplines, and it is hoped that towards a common goal, novel "bench-to-bedside" therapeutics will be developed to improve the lives of, or even cure, patients suffering from dysautonomic syndromes.

Animals↗
PubMed2003

Autonomic failure in neurodegenerative disorders.

Autonomic failure with orthostatic and postprandial hypotension, bowel and bladder disturbances, and sexual dysfunction are frequent, disabling features in patients with the three most prevalent neurodegenerative movement disorders: Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA), and the related neurodegenerative Lewy-body disorder characterized by isolated severe autonomic failure (pure autonomic failure, PAF). All of these disorders have in common the presence of alpha-synuclein in the cytoplasmic precipitates found in neurons in Lewy body disorders or glia in MSA. Autonomic failure with disabling orthostatic hypotension is the clinical hallmark of PAF. It may also be the initial presentation of MSA, making diagnosis difficult. Within a few years, however, MSA patients develop movement disorders, which are differentiated from PD by the paucity of unilateral resting tremor, the lack of response to levodopa, and their rapidly progressive nature, resulting in disability and death in 7 to 8 years. Moderately effective treatment is available for autonomic symptoms, but management of movement disorders remains unsuccessful. Discoveries relevant to physiology and common pathological conditions were initially made in patients with autonomic failure. Meals induce profound hypotension in these patients. Conversely, commonly used nasal decongestants can produce substantial pressor effects. Even 500 mL of water can increase blood pressure by a previously unrecognized sympathetic reflex. Residual sympathetic tone is able to induce sustained supine hypertension in MSA, because it is resolved after ganglionic blockade. These phenomena were not previously recognized because of the buffering capacity of the baroreflex, but were unmasked in autonomic failure patients.

Animals↗
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↗
PubMed2003

Sympathetic control of the circulation in hypertension: lessons from autonomic disorders.

PURPOSE OF THE REVIEW: Inappropriate sympathetic overactivity is consistently observed in patients with essential hypertension. The present review summarizes the recent advances that have been made in our understanding of the role of the sympathetic nervous system in hypertension. RECENT FINDINGS: Studies in patients with autonomic disorders underscore the role of the sympathetic nervous system in the long-term maintenance of hypertension. Abnormalities in the afferent limb of the sympathetic nervous system, in the regulation of central neurons where sympathetic outflow originates, and in the modulation of efferent sympathetic function, can all produce autonomic disorders that are associated with hypertension. More subtle dysfunctions in any of these components have been described in essential hypertension and can contribute to its pathogenesis. These include impaired buffering capacity of arterial baroreflexes, increased central sympathetic outflow, and enhanced norepinephrine release (or decrease reuptake) from sympathetic nerve terminals. Whether genetic polymorphisms of adrenoreceptors are associated with essential hypertension is an area of active research. SUMMARY: Increased sympathetic activity can contribute to sustained hypertension not only because of its hemodynamic effects (increased cardiac output and vascular resistance), but also by altering renal and water handling by the kidney, and by inducing cardiac and vascular remodeling. Antihypertensive agents that directly or indirectly target this sympathetic overactivity may be particularly useful in long-term treatment of essential hypertension.

Animals↗
PubMed2003

Spectrum of autonomic cardiovascular neuropathy in diabetes.

OBJECTIVE: Diabetic patients with incapacitating orthostatic hypotension can have either a "hyperadrenergic" or "hypoadrenergic" presentation. Although the latter is related to overt autonomic neuropathy, the former is proposed to be explained by appropriate autonomic responses. We hypothesize, however, that both conditions are part of a spectrum of autonomic dysfunction. RESEARCH DESIGN AND METHODS: We studied 16 consecutive diabetic patients with preserved renal function referred for incapacitating orthostatic hypotension and characterized their autonomic and neurohumoral cardiovascular regulation. RESULTS: Six patients had a hyperadrenergic orthostatic response: systolic blood pressure fell 42 +/- 15 mmHg, heart rate increased 20 +/- 3 bpm, and plasma norepinephrine increased from 340 +/- 80 to 910 +/- 100 pg/ml. Ten patients had a hypoadrenergic response: systolic blood pressure fell 78 +/- 5 mmHg, heart rate increased only 7 +/- 3 bpm, and norepinephrine increased only from 130 +/- 28 to 230 +/- 40 pg/ml. Vagal (sinus arrhythmia, Valsalva ratio) and sympathetic (response to hyperventilation, postprandial hypotension) responses were impaired in both groups, but to a greater extent in the hypoadrenergic group. Notwithstanding severe orthostatic hypotension, the postural increase in plasma renin was blunted in both groups, more so in the hypoadrenergic group. Despite preserved renal function, patients had mild anemia due to impaired erythropoietin release, as seen in primary cases of autonomic failure. CONCLUSIONS: Our results suggest that diabetic patients presenting with hyperadrenergic orthostatic hypotension have an initial stage of autonomic neuropathy, with overtly abnormal vagal function and early signs of sympathetic impairment. Furthermore, altered renin response can contribute to the patients' orthostatic hypotension.

Arrhythmias, Cardiac↗
PubMed2002

Paradoxical effect of sibutramine on autonomic cardiovascular regulation.

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. METHODS AND RESULTS: In 11 healthy subjects (7 men, age 27+/-2 years, body mass index 23.1+/-0.7 kg/m2), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113+/-3 mm Hg with placebo, 121+/-3 mm Hg with sibutramine (P<0.001 versus placebo), and 111+/-2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position. CONCLUSIONS: The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.

Adrenergic beta-Antagonists↗
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

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↗