Our data support the hypothesis that the sympathetic nervous system stimulates erythropoiesis in humans because anemia is a frequent occurrence in patients with severe autonomic failure and is associated with a blunted erythropoietin response.

Dopamine /3-hydroxyIase (DBH) deficiency is a genetic disorder in which affected patients cannot synthesize norepinephrine, epinephrine, and octopamine in either the central nervous system or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter in their noradrenergic neurons. Neonates with DBH deficiency have had episodic hypothermia, hypoglycemia, and hypotension, but survivors sometimes cope relatively well until late childhood when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension may be so severe that clonic seizures supervene. Most currently recognized patients are young or middle-aged adults. The diagnosis is established by the observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one. (Hypertension 1991;18:l-8)

Abstract-It is believed that adenosine is released in ischemic tissues and contributes to reactive hyperemia. We tested this hypothesis in the human forearm using microdialysis to estimate interstitial and intravascular levels of adenosine and caffeine withdrawal to potentiate endogenous adenosine and determine its effect on reactive hyperemia. Forearm blood flow response to ischemia was measured by air plethysmography before and 60 hours after the last dose of caffeine (250 mg TID for 7 days, nϭ6). Forearm blood flow increased by 274Ϯ66% and 467Ϯ97% after 3 minutes of forearm ischemia, before and during caffeine withdrawal, respectively (PϽ0.05). Thus, caffeine withdrawal enhances reactive hyperemia. To determine the source of adenosine, we measured interstitial adenosine with the use of a microdialysis probe inserted into the flexor digitorum superficialis muscle of the forearm, and we measured intravascular adenosine with the use of a microdialysis probe inserted retrogradely into the medial cubital vein. Dialysate samples were collected at 15-minute intervals during resting, forearm ischemia, and recovery periods. Forearm ischemia failed to increase muscle dialysate concentrations of adenosine but did increase intravascular dialysate adenosine 2.1-fold, from 0.61Ϯ0.12 to 1.28Ϯ0.39 mol/L (PϽ0.01, nϭ8). Intravascular dialysate concentrations of thromboxane B 2 did not increase during ischemia, ruling out platelet aggregation as a source of adenosine. These results support the hypothesis that endogenous adenosine contributes to reactive hyperemia and indicate that the major source of adenosine in the human forearm is intravascular. We speculate that endothelial cells are the source of intravascular adenosine during ischemia. (Hypertension. 1999;33:1453-1457.)Key Words: adenosine Ⅲ ischemia Ⅲ muscle Ⅲ microdialysis L ocal vasodilation is an important protective response to ischemia. This reactive hyperemia, present in all vascular beds with the exception of the kidneys, is largely due to metabolic factors produced by the mismatch between oxygen supply and metabolic demand. Adenosine has been identified as one of the metabolic products involved in this process. The contribution of adenosine to reactive hyperemia has been extensively studied in coronary circulation, 1 and adenosine has also been proposed to contribute to blood flow regulation in several other vascular beds, including skeletal muscle. [2][3][4] Because the actions of adenosine are mediated by cell membrane receptors, its importance in modulating reactive hyperemia will be proportional to the extracellular concentrations it reaches during ischemia. Adenosine is released in tissues when metabolic demands exceed oxygen supply, but extracellular concentrations are limited by efficient mechanisms of cellular uptake and metabolism. Cellular uptake is particularly potent in humans and accounts for the extremely short half-life of adenosine in blood, estimated at Ͻ1 second. 5 Previous attempts to assess how much of an increase in extracellular adenosine is...

Information concerning the frequency, severity, character, location, duration, diurnal pattern of headache and ancillary symptoms were obtained in 25 patients with autonomic failure and 44 control subjects. Precipitating and ameliorating factors were identified. Autonomic failure patients had more head and neck discomfort than controls. Their discomfort was much more likely to localize in the occiput, nape of the neck and shoulder, compared with controls. There was a greater tendency for the discomfort to occur in the morning and after meals. It was sometimes less than 5 min in duration and was often associated with dimming, blurring, or tunnelling of vision. It was provoked by upright posture and relieved by lying down. Patients with severe autonomic failure and orthostatic hypotension often present with a posture-dependent headache or neck pain. Because the relationship of these symptoms to posture is often not recognized, the fact that these findings may signal an underlying autonomic disorder is underappreciated, and the opportunity to consider this aetiology for the headache may be missed.

Patients with autonomic failure secondary to dopamine /3-hydroxylase deficiency lack the enzyme activity necessary for the conversion of dopamine to norepinephrine in sympathetic nerve terminals and the adrenal medulla. These patients have virtually undetectable norepinephrine and epinephrine in plasma and cerebrospinal fluid. The presence of intact sympathetic nerve activity in these patients has been suggested by the enhanced release of dopamine (but not norepinephrine) in response to maneuvers that augment sympathetic outflow in normal subjects. In the present study, we recorded sympathetic nerve traffic by using microneurography in a patient with dopamine /2-hydroxylase deficiency and measured sympathetic neural responses to static exercise, the cold pressor test, and pharmacological alterations of blood pressure. At rest, sympathetic nerve activity was abundant and was modulated in a normal manner by handgrip (+278%), the cold pressor test (+169%), hypotension induced with isoproterenol (+102%), and hypertension induced with phenylephrine (-85%). These results provide the first electrophysiological evidence for intact regulation of sympathetic neural outflow in a patient with dopamine /3-hydroxylase deficiency and suggest that central norepinephrine and epinephrine pathways believed essential for the control of sympathetic neurotransmission in humans may be supplanted by alternative redundant mechanisms. This manuscript from the University of Iowa was sent to Victor J. Dzau, Consulting Editor, for review by expert referees, for editorial decision, and final disposition.Address for correspondence: Robert F. Rea, MD, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242.Received October 21,1988; accepted in revised form September 6, 1989. that indicate normal sympathetic cholinergic and parasympathetic autonomic function. 3Biochemically these patients are characterized by essentially undetectable norepinephrine and epinephrine and greatly elevated dopamine in plasma and cerebrospinal fluid. Plasma levels of dopamine but not norepinephrine increase in response to assumption of upright posture suggesting that dopamine is released from noradrenergic nerve terminals during maneuvers associated with reflex increases of sympathetic nerve activity. 5 We report evidence from intraneural recordings of sympathetic nerve traffic for normal modulation of muscle sympathetic nerve activity (MSNA) in a patient with D/3H deficiency. This is the first electrophysiological demonstration of intact sympathetic neural outflow in this condition. In addition, these results suggest that there are alternative redundant mechanisms independent of central norepinephrine and epinephrine that control sympathetic neural outflow in humans. MethodsThe patient is a 42-year-old white male of Dutch, Scots-Irish, and Cherokee ancestry. He has suffered from lifelong severe orthostatic hypotension, ptosis, nasal stuffiness, and impotence due to retrograde ejaculation. His episodes of orthostatic hypotension