Intravascular source of adenosine during forearm ischemia in humans: implications for reactive hyperemia.

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, n=6). Forearm blood flow increased by 274+/-66% and 467+/-97% after 3 minutes of forearm ischemia, before and during caffeine withdrawal, respectively (P<0.05). 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 0.61+/-0.12 to 1.28+/-0.39 micromol/L (P<0.01, n=8). Intravascular dialysate concentrations of thromboxane B2 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.

The anemia of primary autonomic failure and its reversal with recombinant erythropoietin.

OBJECTIVE: To determine if chronic sympathetic deprivation is associated with anemia and a low erythropoietin response. DESIGN: Survey of the prevalence and characteristics of anemia in patients with severe primary autonomic failure. SETTING: A referral service for autonomic failure in a tertiary teaching hospital. PATIENTS: 84 patients with primary autonomic failure who had symptomatic orthostatic hypotension. INTERVENTION: Open-label trial with human recombinant erythropoietin. RESULTS: Anemia was present in 32 of 84 patients (38%; 95% Cl, 27% to 50%). Plasma norepinephrine levels, measured in patients standing upright, were lower in the patient group with lower hemoglobin levels. Mean values in 22 patients with a hemoglobin level of less than 120 g/L were as follows: hemoglobin, 108 g/L (range, 87 to 118 g/L); hematocrit, 0.33; corrected reticulocyte counts, 0.008; mean corpuscular volume, 89 fL (89 microns 3); serum iron, 16.5 mumol/L (92 micrograms/dL); total iron binding capacity, 43.3 mumol/L (242 micrograms/dL); ferritin, 184 micrograms/L; serum vitamin B12, 410 pmol/L (556 pg/mL); and serum folate, 22.7 nmol/L (10 ng/mL). No relation was found between serum erythropoietin and blood hemoglobin levels. In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia. Therapy with recombinant erythropoietin improved mean hemoglobin levels (from 108 to 133 g/L) in all patients treated (n = 5) at relatively low doses (25 to 50 units/kg body weight, subcutaneously, three times a week). CONCLUSIONS: 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.

The head and neck discomfort of autonomic failure: an unrecognized aetiology of headache.

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.

Hyporeninemic normoaldosteronism in severe autonomic failure.

Sympathetic mechanisms play an important role in the acute regulation of renin release in humans. On the other hand, the effect of chronic sympathetic deprivation on the renin-aldosterone system has not been fully evaluated. We, therefore, studied 24 patients with severe autonomic failure due to pure autonomic failure (n = 14) or to multiple system atrophy (n = 10). Supine plasma renin activity (PRA) was low (0.09 +/- 0.01 ng/(L*s)) and remained virtually unchanged in the upright posture (0.10 +/- 0.01 ng/(L*s)) despite profound orthostatic hypotension to levels that should activate renal baroreceptors. Isoproterenol, at doses that produced significant tachycardia and hypotension, also failed to stimulate PRA. Furthermore, renin-producing cells were absent in the kidneys of two autopsy cases. Norepinephrine depletion alone could not explain these findings because no correlation was found between plasma norepinephrine and PRA, and because PRA was normal in patients with intact sympathetic innervation but congenital absence of norepinephrine. In contrast, supine and upright plasma aldosterone were normal in autonomic failure patients (220 +/- 20 and 440 +/- 70 pmol/L). We speculate that direct sympathetic innervation is essential for the maintenance of renin, perhaps by providing trophic stimuli.

Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation.

Dopamine beta-hydroxylase (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.

Reflex control of sympathetic nerve activity in dopamine beta-hydroxylase deficiency.

Patients with autonomic failure secondary to dopamine beta-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 beta-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 beta-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.

Pressor effect of inhaled ergotamine in orthostatic hypotension.

Treatment of orthostatic hypotension due to autonomic failure frequently necessitates use of pressor agents. Because venous pooling contributes significantly to this disorder, the venoconstrictive properties of ergotamine offer theoretical advantages over pure arteriolar pressor agents. However, the low and erratic bioavailability of oral preparations has hindered the use of ergotamine. Accordingly, the efficacy of inhaled ergotamine tartrate (1 puff, 0.36 mg) was compared to placebo in 8 patients with severe autonomic failure. Blood pressure was monitored in the seated position with an automated device. Ergotamine produced significant increases in systolic (29 +/- 5 mm Hg, p less than 0.01 by analysis of variance) and diastolic (13 +/- 1 mm Hg, p less than 0.001) blood pressures compared to placebo (-9 +/- 5 and -2 +/- 3, respectively). Upright blood pressure 2 hours after administration was significantly greater with ergotamine (119 +/- 8/69 +/- 6 mm Hg) vs placebo (82 +/- 7/59 +/- 5 mm Hg, p less than 0.05). Motionless standing time, a measurement of functional capacity, also improved with ergotamine (200 +/- 58 vs 85 +/- 22 seconds). No side effects were noted, but patients with coronary or peripheral artery disease were excluded. Inhaled ergotamine may provide an effective and practical therapy for disabling orthostatic hypotension due to autonomic failure.