Italo Biaggioni

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome

Roy Freeman • Wouter Wieling • Felicia B. Axelrod • David G. Benditt • Eduardo Benarroch • Italo Biaggioni • William P. Cheshire • Thomas Chelimsky • Pietro Cortelli • Christopher H. Gibbons • David S. Goldstein • Roger Hainsworth • Max J. Hilz • Giris Jacob • Horacio Kaufmann • Jens Jordan • Lewis A. Lipsitz • Benjamin D. Levine • Phillip A. Low • Christopher Mathias • Satish R. Raj • David Robertson • Paola Sandroni • Irwin Schatz • Ron Schondorff • Julian M. Stewart • J. Gert van Dijk

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

BACKGROUND Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the probands family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

The Neuropathic Postural Tachycardia Syndrome

BACKGROUND The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. METHODS We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. RESULTS At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). CONCLUSIONS The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.

The pressor response to water drinking in humans : a sympathetic reflex?

BACKGROUND Water drinking increases blood pressure profoundly in patients with autonomic failure and substantially in older control subjects. The mechanism that mediates this response is not known. METHODS AND RESULTS We studied the effect of drinking tap water on seated blood pressure in 47 patients with severe autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure patients [PAF]). Eleven older controls and 8 young controls served as control group. We also studied the mechanisms that could increase blood pressure with water drinking. Systolic blood pressure increased profoundly with water drinking, reaching a maximum of 33+/-5 mm Hg in MSA and 37+/-7 in PAF mm Hg after 30 to 35 minutes. The pressor response was greater in patients with more retained sympathetic function and was almost completely abolished by trimethaphan infusion. Systolic blood pressure increased by 11+/-2.4 mm Hg in elderly but not in young controls. Plasma norepinephrine increased in both groups. Plasma renin activity, vasopressin, and blood volume did not change in any group. CONCLUSIONS Water drinking significantly and rapidly raises sympathetic activity. Indeed, it raises plasma norepinephrine as much as such classic sympathetic stimuli as caffeine and nicotine. This effect profoundly increases blood pressure in autonomic failure patients, and this effect can be exploited to improve symptoms due to orthostatic hypotension. Water drinking also acutely raises blood pressure in older normal subjects. The pressor effect of oral water is an important yet unrecognized confounding factor in clinical studies of pressor agents and antihypertensive medications.

Primer on the Autonomic Nervous System

Publisher Summary This chapter focuses on the central neural interconnectivity between the brainstem respiratory pattern generator and neural networks governing sympathetic and parasympathetic activity. The respiratory-related alterations in venous return/cardiac output described above also contribute to the respiratory modulation of arterial pressure. However, the fluctuations persist in the working heart brainstem preparation indicating again there is an important central neural component to the coupling. Loss of vagal tone in cardiovascular diseases can be clearly demonstrated by the diminished change in heart rate on administration a vagolytic drug like atropine and also by the loss of respiratory sinus arrhythmia (RSA). The burst of cardiac vagal activity seems to originate centrally at the level of the preganglionic neurons in the nucleus ambiguus that are inhibited during inspiration but excited during postinspiration. There are some key studies that need to be performed. Given its protective role, the site(s) and mechanisms of blockade of cardiac vagal transmission must be identified in cardiovascular disease to allow novel, targeted therapy to be devised.

Differential Expression of Adenosine Receptors in Human Endothelial Cells: Role of A2B Receptors in Angiogenic Factor Regulation

Adenosine has been reported to stimulate or inhibit the release of angiogenic factors depending on the cell type examined. To test the hypothesis that differential expression of adenosine receptor subtypes contributes to endothelial cell heterogeneity, we studied microvascular (HMEC-1) and umbilical vein (HUVEC) human endothelial cells. Based on mRNA level and stimulation of adenylate cyclase, we found that HUVECs preferentially express A2A adenosine receptors and HMEC-1 preferentially express A2B receptors. Neither cells expressed A1 or A3 receptors. The nonselective adenosine agonist 5′-N-ethylcarboxamidoadenosine (NECA) increased expression of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HMEC-1, but had no effect in HUVECs. In contrast, the selective A2A agonist 2-p-(2-carboxyethyl)phenylethylamino-NECA (CGS 21680) had no effect on expression of these angiogenic factors. Cotransfection of each type of adenosine receptors with a luciferase reporter in HMEC-1 showed that A2B receptors, but not A1, A2A, or A3, activated IL-8 and VEGF promoters. These effects were mimicked by constitutively active &agr;Gq, &agr;G12, and &agr;G13, but not &agr;Gs or &agr;Gi1-3. Furthermore, stimulation of phospholipase C indicated coupling of A2B receptors to Gq proteins in HMEC-1. Thus, differential expression of adenosine receptor subtypes contributes to functional heterogeneity of human endothelial cells. A2B receptors, predominantly expressed in human microvascular cells, modulate expression of angiogenic factors via coupling to Gq, and possibly via G12/13.

Adenosine A2B receptors: a novel therapeutic target in asthma?

Adenosine is an endogenous nucleoside that modulates many physiological processes. Its actions are mediated by interaction with specific cell membrane receptors. Four subtypes of adenosine receptor have been cloned: A1, A2A, A2B and A3. Significant advancement has been made in our understanding of the molecular pharmacology and physiological relevance of adenosine receptors but our knowledge of A2B receptors lags behind that of other receptor types. Only recently have potentially important functions been discovered for the A2B receptors, prompting a renewed interest in this receptor type. A2B receptors have been implicated in the regulation of vascular smooth muscle tone, cell growth, intestinal function and neurosecretion. In this review, Igor Feoktistov, Riccardo Polosa, Stephen Holgate and Italo Biaggioni focus on the role of A2B receptors in mast cell activation and the potential relevance of this action on asthma.

Adenosine receptors in regulation of dendritic cell differentiation and function.

Differentiation of functional dendritic cells (DCs) critically depends on the microenvironment. DCs differentiate in hypoxic tumor sites and inflamed or damaged tissue. Because local concentrations of adenosine reach high physiologically relevant levels in these conditions, we assessed the expression of adenosine receptors and the effect of their activation on differentiation of human monocytes and mouse peritoneal macrophages and hematopoietic progenitor cells (HPCs) into myeloid DCs. Stimulation of adenosine receptors skews DC differentiation toward a distinct cell population characterized by expression of both DC and monocyte/macrophage cell surface markers. Pharmacologic analysis and experiments with cells from A(2B) adenosine receptor knockout mice identified A(2B) receptor as the mediator of adenosine effects on DCs. Unlike normal myeloid DCs, adenosine-differentiated DCs have impaired allostimulatory activity and express high levels of angiogenic, pro-inflammatory, immune suppressor, and tolerogenic factors, including VEGF, IL-8, IL-6, IL-10, COX-2, TGF-beta, and IDO. They promoted tumor growth if injected into tumors implanted in mice. Using adenosine desaminase knockout animals, we showed that DCs with proangiogenic phenotype are highly abundant under conditions associated with elevated levels of extracellular adenosine in vivo. Adenosine signaling through A(2B) receptor is an important factor of aberrant DC differentiation and generation of tolerogenic, angiogenic, and proinflammatory cells.

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.

Roy Freeman • Wouter Wieling • Felicia B. Axelrod • David G. Benditt • Eduardo Benarroch • Italo Biaggioni • William P. Cheshire • Thomas Chelimsky • Pietro Cortelli • Christopher H. Gibbons • David S. Goldstein • Roger Hainsworth • Max J. Hilz • Giris Jacob • Horacio Kaufmann • Jens Jordan • Lewis A. Lipsitz • Benjamin D. Levine • Phillip A. Low • Christopher Mathias • Satish R. Raj • David Robertson • Paola Sandroni • Irwin Schatz • Ron Schondorff • Julian M. Stewart • J. Gert van Dijk

Cardiovascular and respiratory effects of adenosine in conscious man. Evidence for chemoreceptor activation.

The cardiovascular and respiratory effects of intravenous adenosine were studied in conscious normal volunteers. Bolus injections of adenosine increased systolic and diastolic pressures initially (+15 and +13 mm Hg after 100 μg/kg) followed by a subsequent reduction in systolic and diastolic pressures (-12 and -16 mm Hg). Heart rate increased during trough blood pressure (R-R interval shortening of 298 msec after 100 μg/kg). Adenosine steady-state infusions increased heart rate ( + 30 beats/min during 140 μg/kg/min), systolic pressure ( + 16 mm Hg), and pulse pressure ( + 21 mm Hg) but decreased diastolic pressure slightly (- 5 mm Hg), resulting in no significant change in mean arterial pressure. Adenosine stimulated respiration, resulting in decreased Paco2 (41 to 31 mm Hg), increased Pao2 (101 to 113 mm Hg), and increased pH (7.42 to 7.50). The increased ventilation was not explained by bronchoconstriction, hypotension, or hypoxia. The observed pressor and tachycardic effects are mediated through reflex autonomic mechanisms since they are completely abolished in patients with severe autonomic failure. These autonomic mechanisms probably involve chemoreceptor activation since adenosine is pressor when infused in the aortic arch proximal to the origin of the carotid arteries but depressor when infused in the descending aorta. It is concluded that the hemodynamic and respiratory effects of adenosine observed in normal volunteers are in part due to chemoreceptor stimulation. These findings raise the possibility that adenosine is an endogenous modulator of respiration in man.