Cyndya Shibao

Autonomic Contribution to Blood Pressure and Metabolism in Obesity

Obesity is associated with alterations in the autonomic nervous system that may contribute to the increase in blood pressure and resting energy expenditure present in this condition. To test this hypothesis, we induced autonomic withdrawal with the ganglionic blocker trimethaphan in 10 lean (32±3 years) and 10 obese (35±3 years) subjects. Systolic blood pressure fell more in obese compared with lean subjects (−17±3 versus −11±1 mm Hg; P=0.019) because of a greater decrease in total peripheral resistance (−310±41 versus 33±78 dynes/sec/cm−5; P=0.002). In contrast, resting energy expenditure decreased less in obese than in lean subjects, (−26±21 versus −86±15 kcal per day adjusted by fat-free mass; P=0.035). We confirmed that the autonomic contribution to blood pressure was greater in obesity after including additional subjects with a wider range of blood pressures. Systolic blood pressure decreased −28±4 mm Hg (95% CI: −38 to −18.0; n=8) in obese hypertensive subjects compared with lean (−9±1 mm Hg; 95% CI: −11 to −6; n=22) or obese normotensive subjects (−14±2 mm Hg; 95% CI: −18 to −10; n=20). After removal of autonomic influences, systolic blood pressure remained higher in obese hypertensive subjects (109±3 versus 98±2 mm Hg in lean and 103±2 mm Hg in obese normotensive subjects; P=0.004) suggesting a role for additional factors in obesity-associated hypertension. In conclusion, sympathetic activation induced by obesity is an important determinant to the blood pressure elevation associated with this condition but is not effective in increasing resting energy expenditure. These results suggest that the sympathetic nervous system could be targeted in the treatment of obesity-associated hypertension.

Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders

Postural tachycardia syndrome (POTS) is a disabling condition that commonly affects otherwise normal young females. Because these patients can present with a flushing disorder, we hypothesized that mast cell activation (MCA) can contribute to its pathogenesis. Here we describe POTS patients with MCA (MCA+POTS), diagnosed by episodes of flushing and abnormal increases in urine methylhistamine, and compared them to POTS patients with episodic flushing but normal urine methylhistamine and to normal healthy age-matched female controls. MCA+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse. In addition, patients were disabled by orthostatic intolerance and a characteristic hyperadrenergic response to posture, with orthostatic tachycardia (from 79±4 to 114±6 bpm), increased systolic blood pressure on standing (from 117±5 to 126±7 mm Hg versus no change in POTS controls), increased systolic blood pressure at the end of phase II of the Valsalva maneuver (157±12 versus 117±9 in normal controls and 119±7 mm Hg in POTS; P=0.048), and an exaggerated phase IV blood pressure overshoot (50±10 versus 17±3 mm Hg in normal controls; P<0.05). In conclusion, MCA should be considered in patients with POTS presenting with flushing. These patients often present with a typical hyperadrenergic response, but &bgr;-blockers should be used with great caution, if at all, and treatment directed against mast cell mediators may be required.

Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans

Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by ≈15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. NG-Monomethyl-l-arginine (250 &mgr;g/kg per minute IV) increased mean BP by 6±3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21±8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11±4.5 versus 30±2.3 mm Hg in normotensive individuals; P<0.005). Thus, we report a novel approach to preferentially evaluate the role of eNO on BP control in normal and disease states. Our results suggest that eNO is one of the most potent metabolic determinants of BP in humans, tonically restraining it by ≈30 mm Hg.

Acarbose, an α-Glucosidase Inhibitor, Attenuates Postprandial Hypotension in Autonomic Failure

Postprandial hypotension is an important clinical condition that predisposes to syncope, falls, angina, and cerebrovascular events. The magnitude of the fall in blood pressure after meals depends on enteric glucose availability. We hypothesized that acarbose, an &agr;-glucosidase inhibitor that decreases glucose absorption in the small intestine, would attenuate postprandial hypotension. Acarbose or placebo was given 20 minutes before a standardized meal in 13 patients with postprandial hypotension in the setting of autonomic failure (age: 65±2.64 years; body mass index: 25±1.08 kg/m2; supine plasma norepinephrine: 110±26.6 pg/mL). Four patients were studied in a single-blind protocol and 9 patients in a double-blind, randomized, crossover fashion. Patients were studied supine, and blood pressure, heart rate, and neuroendocrine parameters were obtained at baseline and for 90 minutes after meal intake. After adjusting for potential confounders, acarbose significantly attenuated the postprandial fall in systolic and diastolic blood pressures by 17 mm Hg (95% CI: 7 to 28; P=0.003) and 9 mm Hg (95% CI: 5 to 14; P=0.001), respectively. Furthermore, acarbose effectively reduced plasma levels of insulin, a known vasodilator, by 11 &mgr;U/mL (95% CI: 5 to 18; P=0.001) compared with placebo. After adjusting for insulin levels, the attenuation of postprandial hypotension by acarbose remained significant, indicating that additional mechanisms contribute to this effect. In conclusion, 100 mg of acarbose successfully improved postprandial hypotension in patients with severe autonomic failure. This effect is not explained solely by a reduction in insulin levels.

Nocturnal Blood Pressure Dipping in the Hypertension of Autonomic Failure

Blood pressure (BP) normally decreases during the night. Absence of this phenomenon (nondipping) is associated with increased cardiovascular risk. Altered autonomic and endocrine circadian rhythms are suspected to play a role. Patients with peripheral autonomic failure offer a unique opportunity to study this phenomenon, because ≈50% develop supine hypertension despite very low autonomic function. The purpose of this study was to define the prevalence of dipping in these patients and to determine whether dipping is associated with less severe autonomic impairment or exaggerated nocturnal sodium excretion. We collected BP and urine from 8:00 pm to 8:00 am in 41 peripheral autonomic failure patients with supine hypertension. Dipping (systolic BP fall ≥10% during 12 am to 6 am from baseline [8 pm to 10 pm]) occurred in 34% of patients, with an average decrease of −44±4 mm Hg at 4 am. Systolic BP, averaged from 12 am to 6 am, decreased to normotensive levels in 50% (n=7) of dippers and 15% (n=7) of nondippers. There were no significant differences in the severity of autonomic failure, nocturnal diuresis, or natriuresis (0.18±0.01 in dippers versus 0.18±0.01 mEq/mg of creatinine in nondippers; P=0.522) between groups. At 8:00 am, orthostatic hypotension was similar between groups (−84/−35±9/4 mm Hg in dippers versus −93/−39±6/3 mm Hg in nondippers; P=0.356 for systolic BP). In conclusion, dipping was observed in one third of patients with peripheral autonomic failure, so that a significant percentage of patients would not require treatment for supine hypertension. Dipping was not associated with increased nocturnal urinary sodium or volume excretion or less severe autonomic failure. Thus, mechanisms independent of autonomic pathways contribute to BP dipping in these patients.

Comparative Efficacy of Yohimbine Against Pyridostigmine for the Treatment of Orthostatic Hypotension in Autonomic Failure

Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the &agr;-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6±3 mm Hg [95% CI: −5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.

Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function

Atomoxetine, a selective norepinephrine transporter blocker, could increase blood pressure by elevating norepinephrine concentration in peripheral sympathetic neurons. This effect may be masked in healthy subjects by central sympatholytic mechanisms. To test this hypothesis we studied the pressor effect of 18 mg of atomoxetine (pediatric dose) in 21 patients with damage of the central (10 subjects) and peripheral (11 subjects) autonomic nervous system. Atomoxetine was administered in a randomized, crossover, placebo-controlled fashion, and blood pressure and heart rate were measured at baseline and for 60 minutes after drug intake. Atomoxetine acutely increased seated and standing systolic blood pressure in patients with central autonomic failure by 54±26 (mean±standard deviation; P=0.004) and 45±23 mm Hg (P=0.016), respectively, as compared with placebo. At the end of the observation period the mean seated systolic blood pressure in the atomoxetine group was in the hypertensive range (149±26, range 113 to 209 mm Hg). However, in patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response; seated and standing systolic blood pressure increased by 4±18 mm Hg (P=0.695) and 0.6±8 mm Hg (P=0.546) with atomoxetine as compared with placebo. In conclusion, atomoxetine induces a dramatic increase in blood pressure in patients with central autonomic failure even at very low doses. These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug. Caution should be exercised when this medication is used in patients with milder form of autonomic impairment.

ASH Position Paper: Evaluation and Treatment of Orthostatic Hypotension

This paper provides recommendations on the treatment of orthostatic hypotension (OH) as reviewed by the American Society of Hypertension. It focuses on recent reports on the evaluation and management of OH and provides practical advice for clinicians on how to screen, diagnose, and treat patients using behavioral, nonpharmacologic, and pharmacologic strategies. The authors also provide a stepwise approach on how to apply new findings to successfully control OH and reduce the risk of syncope and falls in these patients. Treatment of OH is also discussed in special situations such as in hypertensive and hospitalized patients. It should be noted, however, that research in this area is mostly limited to studies in small numbers of patients. Unfortunately, the trials of the type needed to develop evidence‐based guidelines are not available for this condition.

Angiotensin II, Independent of Plasma Renin Activity, Contributes to the Hypertension of Autonomic Failure

At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Although the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable, suggesting renin–angiotensin (Ang) pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that Ang II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating Ang II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/mL, n=11) compared with matched healthy controls (27±4 pg/mL, n=10; P=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/mL per hour, respectively; P=0.449). To determine the contribution of Ang II to supine hypertension in these patients, we administered the AT1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mm Hg at 6 hours after administration (P<0.05), decreased nocturnal urinary sodium excretion (P=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of captopril on supine blood pressure in a subset of these patients. These findings suggest that Ang II formation in autonomic failure is independent of plasma renin activity, and perhaps Ang-converting enzyme. Furthermore, these studies suggest that elevations in Ang II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT1 receptor blockers for treatment of these patients.

Clonidine for the Treatment of Supine Hypertension and Pressure Natriuresis in Autonomic Failure

Patients with autonomic failure are disabled by orthostatic hypotension, which can be worsened by the nighttime pressure natriuresis induced by associated supine hypertension. Several pharmacological agents are available that effectively reduce nighttime hypertension, but none of them prevent pressure natriuresis. Because hypertension of autonomic failure can be driven by residual sympathetic tone, we hypothesized that clonidine would be effective in reducing blood pressure (BP) and nocturnal natriuresis. Therefore, we determined the effect of placebo, 0.1 mg clonidine, and 0.1-mg/h nitroglycerin transdermal patch on supine BP, orthostatic hypotension, and pressure natriuresis in 23 patients with primary autonomic failure and supine hypertension. Medications were given at 8:00 pm, and BP was recorded every 2 hours for 12 hours. The maximal decrease in BP was seen 6 to 8 hours after drug administration and was similar to clonidine and nitroglycerin (−29±9 and −30±10 mm Hg, respectively), as was the average fall in BP throughout the night. However, only clonidine effectively reduced nocturnal natriuresis (−0.09 mmol/mg Cr; 95% CI, −0.13 to −0.04; P=0.004), but this was not associated with improvement in morning orthostatic hypotension because of a residual hypotensive effect. The decrease in BP induced by clonidine was modestly but significantly correlated with the magnitude of residual sympathetic tone determined in 10 subjects by the fall in BP induced by ganglionic blockade (r=0.66; P=0.043). These results are consistent with residual sympathetic tone contributing to supine hypertension in autonomic failure, which can be targeted with clonidine to decrease BP and nocturnal natriuresis.