A Longitudinal Skin Biopsy Study of Phosphorylated Alpha-Synuclein in a Patient With Parkinson Disease and Orthostatic Hypotension.

The aim of our study was to assess the distribution of phosphorylated α-synuclein (p-syn) deposits in a patient affected by early stage Parkinson disease and orthostatic hypotension through a longitudinal skin biopsy study. We found widespread p-syn spatial diffusion from deep autonomic dermis nerve bundles to autonomic terminals, suggesting a centrifugal spread of p-syn from ganglia to the innervation target structures. Furthermore, the case suggests the possibility of discriminating synucleinopathies at an early stage of disease by means of skin biopsy. If confirmed, these data support skin biopsy as a useful and promising tool for the diagnosis, longitudinal evaluation, and pathological understanding of Parkinson disease.

α 2-Adrenoceptors: Challenges and Opportunities-Enlightenment from the Kidney.

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α 2-adrenoceptors (α 2-ARs) in skin-lightening experiments in the frog. Now α 2-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α 2-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α 2-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α 2-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α 2-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α 2-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α 2-ARs activate prohypertensive biochemical systems. While investigating the role of α 1-adrenoceptors (α 1-ARs) versus α 2-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α 1-ARs suppress the postjunctional expression of α 2-ARs. Here, we describe how this finding relates to a broader understanding of the role of α 2-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α 2-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.

Long-term trends in myocardial sympathetic innervation and function in synucleinopathies.

INTRODUCTION: Parkinson disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA) are characterized by intra-cerebral deposition of the protein alpha-synuclein and are termed synucleinopathies. Lewy body synucleinopathies involve decreased cardiac sympathetic innervation and functional abnormalities in residual noradrenergic terminals. This observational, retrospective, cohort study describes long-term trends in indices of cardiac sympathetic innervation and function in synucleinopathies. METHODS: Patients with PD (N = 31), PAF (N = 9), or MSA (N = 9) underwent repeated 18F-dopamine positron emission tomography (median follow-up 3.5 years). Interventricular septal 18F-dopamine-derived radioactivity 8 min after tracer injection (8' Radioactivity) was used as an index of sympathetic innervation and the slope of mono-exponential decline of radioactivity between 8 and 25 min (k8'-25') as an index of intraneuronal vesicular storage. Healthy volunteers (HVs) (N = 33) and individuals at high risk of PD (N = 15) were controls. RESULTS: Upon initial evaluation the groups with PD and orthostatic hypotension (OH), PAF, or PD and no OH had low mean 8' Radioactivity compared to HVs (p < 0.0001, p = 0.0002, p = 0.006) and had elevated k8'-25' (p = 0.0007, p = 0.007, p = 0.06). There was no significant difference between MSA and HVs. In PD 8' Radioactivity decreased by a median of 4% per year and did not decrease in MSA. k8'-25' values did not change during follow-up in any group. CONCLUSIONS: Neuroimaging evidence of decreased vesicular uptake in cardiac sympathetic nerves is present upon initial evaluation of patients with Lewy body synucleinopathies and may provide a biomarker of catecholaminergic dysfunction early in the disease process.

Alpha-Synuclein Deposition Within Sympathetic Noradrenergic Neurons Is Associated With Myocardial Noradrenergic Deficiency in Neurogenic Orthostatic Hypotension.

Lewy body diseases involve neurogenic orthostatic hypotension (nOH), cardiac noradrenergic deficiency, and deposition of the protein AS (alpha-synuclein) in sympathetic ganglion tissue. Mechanisms linking these abnormalities are poorly understood. One link may be AS deposition within sympathetic neurons. We validated methodology to quantify AS colocalization with TH (tyrosine hydroxylase), a marker of sympathetic noradrenergic innervation, and assessed associations of AS/TH colocalization with myocardial norepinephrine content and cardiac sympathetic neuroimaging data in nOH. Postmortem sympathetic ganglionic AS/TH colocalization indices and myocardial norepinephrine contents were measured in 4 Lewy body and 3 rare non-Lewy body nOH patients. Sixteen Lewy body and 11 non-Lewy body nOH patients underwent in vivo skin biopsies and thoracic 18F-dopamine positron emission tomographic scanning, with cutaneous colocalization indices expressed versus cardiac 18F-dopamine-derived radioactivity. Ganglionic AS/TH colocalization indices were higher and myocardial norepinephrine lower in Lewy body than non-Lewy body nOH ( P=0.0020, P=0.014). The Lewy body nOH group had higher AS/TH colocalization indices in skin biopsies and lower myocardial 18F-dopamine-derived radioactivity than did the non-Lewy body nOH group ( P<0.0001 each). All Lewy body nOH patients had colocalization indices >1.5 in skin biopsies and 18F-dopamine-derived radioactivity <6000 nCi-kg/cc-mCi, a combination not seen in non-Lewy body nOH patients ( P<0.0001). In Lewy body nOH, AS deposition in sympathetic noradrenergic nerves is related to postmortem neurochemical and in vivo neuroimaging evidence of myocardial noradrenergic deficiency. These associations raise the possibility that intraneuronal AS deposition plays a pathophysiological role in the myocardial sympathetic neurodegeneration attending Lewy body nOH.

Skin Nerve Phosphorylated α-Synuclein Deposits in Parkinson Disease With Orthostatic Hypotension.

This study aimed to investigate phosphorylated α-synuclein (p-syn) in autonomic skin nerves of Parkinson disease (PD) patients with and without orthostatic hypotension (OH). We studied 28 PD patients with normal corrected Mini-Mental State Examination including 14 patients with neurogenic OH (PD + OH) and 14 matched patients did not complain of OH (PD - OH); 7 of whom were re-evaluated over a follow-up period (4 ± 2 years). Skin biopsy was performed in proximal and distal sites. PD + OH patients showed a higher p-syn deposition than PD - OH, with widespread autonomic cholinergic and adrenergic skin nerve involvement. Over the follow-up period, PD - OH patients showed an increase in motor dysfunction scores without autonomic symptoms and a slight increase of skin p-syn deposition but still lower than PD + OH, mainly restricted to adrenergic fibers of skin vessels (SV). In summary, PD + OH patients showed a wide involvement of p-syn deposits in autonomic cholinergic and adrenergic skin nerves compared with PD - OH, and PD - OH patients showed a lower load of skin p-syn restricted to adrenergic fibers of SV still persisting over the follow-up period. The data supported a different pathogenesis between PD + OH and PD - OH and may help to identify a specific diagnostic trait for PD + OH.

Prolonged bed rest impairs rapid CPI-17 phosphorylation and contraction in rat mesenteric resistance arteries to cause orthostatic hypotension.

Prolonged bed rest (PBR) causes orthostatic hypotension (OH). Rapid constriction of splanchnic resistance arteries in response to a sudden increase in sympathetic tone contributes to the recovery of orthostatic arterial pressure upon standing. However, the molecular mechanism of PBR-induced dysfunction in arterial constriction is not fully understood. Previously, we showed that CPI-17, a regulatory protein for myosin phosphatase, mediates α1A-adrenergic receptor-induced rapid contraction of small mesenteric arteries. Here, we tested whether PBR associated with OH affects the α1-adrenergic receptor-induced CPI-17 signaling pathway in mesenteric arteries using rats treated by head-down tail-suspension hindlimb unloading (HDU), an experimental OH model. In normal anesthetized rats, mean arterial pressure (MAP) rapidly reduced upon 90° head-up tilt from supine position and then immediately recovered without change in heart rate, suggesting a rapid arterial constriction. On the other hand, after a 4-week HDU treatment, the fast orthostatic MAP recovery failed for 1 min. Alpha1A subtype-specific antagonist suppressed the orthostatic MAP recovery with a small decrease in basal blood pressure, whereas non-specific α1-antagonist prazosin strongly reduced both basal MAP and orthostatic recovery. The HDU treatment resulted in 68% reduction in contraction in parallel with 83% reduction in CPI-17 phosphorylation in denuded mesenteric arteries 10 s after α1-agonist stimulation. The treatment with either Ca2+-release channel opener or PKC inhibitor mimicked the deficiency in HDU arteries. These results suggest that an impairment of the rapid PKC/CPI-17 signaling pathway downstream of α1A-adrenoceptors in peripheral arterial constriction, as an end organ of orthostatic blood pressure reflex, is associated with OH in prolonged bed rest patients.

Comorbilidad Médica y Criterios de uso de antipsicóticos en ancianos / No disponible

Los antipsicóticos son el tratamiento de elección de los síntomas psicóticos en la población anciana. También se emplean para el tratamiento de otros diagnósticos como depresión, trastorno bipolar, ansiedad grave o insomnio. La eficacia entre los distintos antipsicóticos es similar, pero en la población anciana es el perfil de efectos secundarios lo que condiciona la prescripción de un antipsicótico u otro. En este artículo se realiza una puesta al día del empleo de antipsicóticos en ancianos, incidiendo en las diferencias entre antipsicóticos típicos y atípicos, así como entre los distintos antipsicóticos atípicos entre sí. Se han revisado los principales efectos adversos de estos medicamentos en la vejez, enfatizando en los efectos cardio y cerebrovascular tanto en ancianos con enfermedad mental como en ancianos con enfermedades neurodegenerativas

Antipsychotics are the first choice for the psychotic symptoms in the elderly. These drugs are also employed other diagnosis such as depression, bipolar disorder, severe anxiety or insomnia. The efficacy appears to be similar for all antipsychotics. In the elderly, adverse effects determine the use of a specific antipsychotic. In this article we expose an update on the use of antipsychotics in the elderly, focusing in the differences between typical and atypical antipsychotics and among all the atypicals. The main adverse effects of these drugs in the elderly are reviewed, with an special focus on the cardio and cerebrovascular adverse effects, both in patients with mental illness and in patients with neurodegenerative disorders

Diagnosing and treating neurogenic orthostatic hypotension in primary care.

In response to a change in posture from supine or sitting to standing, autonomic reflexes normally maintain blood pressure (BP) by selective increases in arteriovenous resistance and by increased cardiac output, ensuring continued perfusion of the central nervous system. In neurogenic orthostatic hypotension (NOH), inadequate vasoconstriction and cardiac output cause BP to drop excessively, resulting in inadequate perfusion, with predictable symptoms such as dizziness, lightheadedness and falls. The condition may represent a central failure of baroreceptor signals to modulate cardiovascular function, a peripheral failure of norepinephrine release from cardiovascular sympathetic nerve endings, or both. Symptomatic patients may benefit from both non-pharmacologic and pharmacologic interventions. Among the latter, two pressor agents have been approved by the US Food and Drug Administration: the sympathomimetic prodrug midodrine, approved in 1996 for symptomatic orthostatic hypotension, and the norepinephrine prodrug droxidopa, approved in 2014, which is indicated for the treatment of symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure). A wide variety of off-label options also have been described (e.g. the synthetic mineralocorticoid fludrocortisone). Because pressor agents may promote supine hypertension, NOH management requires monitoring of supine BP and also lifestyle measures to minimize supine BP increases (e.g. head-of-bed elevation). However, NOH has been associated with cognitive impairment and increases a patient's risk of syncope and falls, with the potential for serious consequences. Hence, concerns about supine hypertension - for which the long-term prognosis in patients with NOH is yet to be established - must sometimes be balanced by the need to address a patient's immediate risks.

[Orthostatic reactions in prognosis of the risks of arterial hypertension as a component of metabolic syndrome].

It was shown that parameters of metabolic syndrome as predictors of lethal vascular outcomes of arterial hypertension (AH) in Belarus are significantly different fiom those proposed in WHO recommendations (1999). The glucose level of informative value in WHO recommendations is 6.1 mmol/l versus 5.6 mmol/l in Belarus, total cholesterol 5.0 and 5.9 mmol/l respectively. A more detailed verification of the value of both parameters is needed for the patients in Belarus and Russia depending on age and sex using non-linear models. We used a comprehensive approach to prognosis of the risk of vascular lethal outcomes of AH as a component of metabolic syndrome with the evaluation of results of clinical and laboratory examination as well as orthostatic reactions in patients of different age groups. Construction of the prognostic algorithm "Classification tree" taking account of orthostatic reactions enhances the correctness of lethal outcome prognosis up to 81.8%. The study revealed the prognostic value of systolic and diastolic arterial pressure in the supine position (15 min of active aortostatic sample) for prognostication of vascular lethal outcomes. Further studies are needed on the role of orthostatic reactions in AH patients of old age together with clinical and laboratory parameters in the prognostication of outcomes of various cardiovascular diseases.

Slow breathing as a means to improve orthostatic tolerance: a randomized sham-controlled trial.

Endogenous oscillations in blood pressure (BP) and cerebral blood flow have been associated with improved orthostatic tolerance. Although slow breathing induces such responses, it has not been tested as a therapeutic strategy to improve orthostatic tolerance. With the use of a randomized, crossover sham-controlled design, we tested the hypothesis that breathing at six breaths/min (vs. spontaneous breathing) would improve orthostatic tolerance via inducing oscillations in mean arterial BP (MAP) and cerebral blood flow. Sixteen healthy participants (aged 25 ± 4 yr; mean ± SD) had continuous beat-to-beat measurements of middle cerebral artery blood velocity (MCAv), BP (finometer), heart rate (ECG), and end-tidal carbon dioxide partial pressure during an incremental orthostatic stress test to presyncope by combining head-up tilt with incremental lower-body negative pressure. Tolerance time to presyncope was improved (+15%) with slow breathing compared with spontaneous breathing (29.2 ± 5.4 vs. 33.7 ± 6.0 min; P < 0.01). The improved tolerance was reflected in elevations in low-frequency (LF; 0.07-0.2 Hz) oscillations of MAP and mean MCAv, improved metrics of dynamic cerebrovascular control (increased LF phase and reduced LF gain), and a reduced rate of decline for MCAv (-0.60 ± 0.27 vs. -0.99 ± 0.51 cm·s(-1)·min(-1); P < 0.01) and MAP (-0.50 ± 0.37 vs. -1.03 ± 0.80 mmHg/min; P = 0.01 vs. spontaneous breathing) across time from baseline to presyncope. Our findings show that orthostatic tolerance can be improved within healthy individuals with a simple, nonpharmacological breathing strategy. The mechanisms underlying this improvement are likely mediated via the generation of negative intrathoracic pressure during slow and deep breathing and the related beneficial impact on cerebrovascular and autonomic function.

Initial orthostatic hypotension and cerebral blood flow regulation: effect of α1-adrenoreceptor activity.

We examined the hypothesis that α(1)-adrenergic blockade would lead to an inability to correct initial orthostatic hypotension (IOH) and cerebral hypoperfusion, leading to symptoms of presyncope. Twelve normotensive humans (aged 25 ± 1 yr; means ± SE) attempted to complete a 3-min upright stand, 90 min after the administration of either α(1)-blockade (prazosin, 1 mg/20 kg body wt) or placebo. Continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv; Doppler), blood pressure (finometer), heart rate, and end-tidal Pco(2) were obtained. Compared with placebo, the α(1)-blockade reduced resting mean arterial blood pressure (MAP) (-15%; P < 0.01); MCAv remained unaltered (P ≥ 0.28). Upon standing, although the absolute level of MAP was lower following α(1)-blockade (39 ± 10 mmHg vs. 51 ± 14 mmHg), the relative difference in IOH was negligible in both trials (mean difference in MAP: 2 ± 2 mmHg; P = 0.50). Compared with the placebo trial, the declines in MCAv and Pet(CO(2)) during IOH were greater in the α(1)-blockade trial by 12 ± 4 cm/s and 4.4 ± 1.3 mmHg, respectively (P ≤ 0.01). Standing tolerance was markedly reduced in the α(1)-blockade trial (75 ± 17 s vs. 180 ± 0 s; P < 0.001). In summary, while IOH was little affected by α(1)-blockade, the associated decline in MCAv was greater in the blockade condition. Unlike in the placebo trial, the extent of IOH and cerebral hypoperfusion failed to recover toward baseline in the α(1)-blockade trial leading to presyncope. Although the development of IOH is not influenced by the α(1)-adrenergic receptor pathway, this pathway is critical in the recovery from IOH to prevent cerebral hypoperfusion and ultimately syncope.

Abordaje terapéutico de los síntomas no motores de la enfermedad de Parkinson / Therapeutic management of the non-motor symptoms in Parkinson's disease

Introducción. La enfermedad de Parkinson (EP) es una entidad compleja con una sintomatología diversa que presenta, además de los clásicos síntomas motores, un amplio número de síntomas no motores. Estos síntomas son muy prevalentes desde el inicio de la enfermedad e incluso pueden preceder en el tiempo a los síntomas motores (estreñimiento, alteración del olfato, trastorno de conducta del sueño REM) actuando como marcadores precoces de la enfermedad. Causan importante impacto en la calidad de vida de los enfermos con EP. Pueden ser los síntomas más incapacitantes para el paciente. Por todo ello, precisan de un manejo adecuado que mejore el bienestar de nuestros pacientes. Objetivo. Dar una visión actualizada del tratamiento de los síntomas no motores más prevalentes de la EP. Desarrollo. Se describen los síntomas no motores (vegetativos, trastornos del sueño, apatía) más prevalentes y discapacitantes de la enfermedad de Parkinson y se hace una revisión actualizada de su tratamiento. Conclusión: La alteración que la enfermedad produce en otros sistemas distintos al dopaminérgico causa un amplio número de síntomas distintos a los motores. Su mejor conocimiento permitirá diagnosticar y optimizar el tratamiento de estos síntomas, reforzando el bienestar de nuestros pacientes (AU)

Introduction. Parkinson's disease (PD) is a complex condition with a variety of symptoms, including a large number of nonmotor symptoms, in addition to the classic motor symptoms. These symptoms are highly prevalent from the onset of the disease and may even appear earlier than the motor symptoms (constipation, altered sense of smell, REM sleep behaviour disorder) and act as early markers of the disease. They have a significant impact on the quality of life of patients with PD and can be the most disabling symptoms for the patient. As a result, they need adequate management that improves our patients’ welfare. Aims. The objective of this study is to offer an updated view of the most prevalent non-motor symptoms of PD. Development. We describe the most prevalent and disabling non-motor symptoms (vegetative, sleep disorders, apathy) of Parkinson's disease and we also conduct a review of the state-of-the-art in its treatment. Conclusions. The alterations that the illness produces in systems other than the dopaminergic system cause a large number of symptoms in addition to the motor ones. A better understanding of them will make it possible to diagnose and optimise the treatment of these symptoms, thereby boosting our patients' welfare (AU)

Influence of ABCB1 (P-glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: A single nucleotide polymorphism in ABCB1, which encodes P-glycoprotein, has retrospectively been associated with symptoms of nortriptyline-induced postural hypotension in depressed patients. This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made. WHAT THIS STUDY ADDS: In a prospective study of healthy volunteers homozygous for ABCB1 (1236-2677-3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change. No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes. The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline. AIMS To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. METHODS: Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography. RESULTS: There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min(-1) , P = 0.02). At t(max) at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min(-1) on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min(-1) on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group. CONCLUSION: The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.

Cortical oxygen supply during postural hypotension is further decreased in Alzheimer's disease, but unrelated to cholinesterase-inhibitor use.

Cerebrovascular function and structure of the cortical cerebral microvessels are profoundly altered in patients with Alzheimer's disease (AD). The functional hemodynamic consequences of such changes, however, remain essentially unknown. Cholinesterase inhibitors (ChEIs) potentially affect brain perfusion through either augmentation or inhibition of cerebral vasodilatation. This study investigated the cerebrovascular regulation during postural changes in AD before and after treatment with the ChEI galantamine. In 21 AD patients and 20 controls, blood pressure (BP--Finapres), frontal cortical oxygenation (near-infrared-spectroscopy), and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) were measured following a hypotensive challenge induced by postural change. In AD, measurements were repeated after 10 (SD 4) weeks of galantamine. Baseline cerebrovascular resistance was higher in AD (AD 2.83 (0.87) mmHg/cm/s, control 2.24 (1.3) mmHg/cm/s, p=0.010). 13 AD patients and 17 controls had a sufficiently large postural drop in BP (> 10 mmHg). AD patients had a larger postural decline in the frontal cortical concentration of total hemoglobin (Delta [tHb] AD=1.03 (0.70) micromol/l, control =0.30 (0.90) micromol/l, p=0.015). Moreover, the reduction in oxygenated hemoglobin was 57% larger in AD (p=0.085). Unexpectedly, the postural changes in BP were smaller in AD. Galantamine treatment affected neither orthostatic BP nor the decrease in [tHb]. In conclusion, even for moderate orthostatic hypotension during commonly occurring postural changes, cerebral cortical tissue perfusion declined more in AD, suggesting increased ischemic vulnerability of the brain. Galantamine neither improved nor impaired cerebrovascular regulation.

Angiotensin II type 1 receptor blockade corrects cutaneous nitric oxide deficit in postural tachycardia syndrome.

Low-flow postural tachycardia syndrome (POTS) is associated with increased plasma angiotensin II (ANG II) and reduced neuronal nitric oxide (NO), which decreases NO-dependent vasodilation. We tested whether the ANG II type 1 receptor (AT(1)R) antagonist losartan would improve NO-dependent vasodilation in POTS patients. Furthermore, if the action of ANG II is dependent on NO, then the NO synthase inhibitor nitro-L-arginine (NLA) would reverse this improvement. We used local heating of the skin of the left calf to 42 degrees C and laser-Doppler flowmetry to assess NO-dependent conductance [percent maximum cutaneous vascular conductance (%CVC(max))] in 12 low-flow POTS patients aged 22.5 +/- 0.8 yr and in 15 control subjects aged 22.0 +/- 1.3 yr. After measuring the baseline local heating response at three separate sites, we perfused individual intradermal microdialysis catheters at those sites with 2 microg/l losartan, 10 mM NLA, or losartan + NLA. The predrug heat response was reduced in POTS, particularly the plateau phase reflecting NO-dependent vasodilation (50 +/- 5 vs. 91 +/- 7 %CVC(max); P < 0.001 vs. control). Losartan increased baseline flow in both POTS and control subjects (from 6 +/- 1 to 21 +/- 3 vs. from 10 +/- 1 to 21 +/- 2 %CVC(max); P < 0.05 compared with predrug). The baseline increase was blunted by NLA. Losartan increased the POTS heat response to equal the control subject response (79 +/- 7 vs. 88 +/- 6 %CVC(max); P = 0.48). NLA decreased both POTS and control subject heat responses to similar conductances (38 +/- 4 vs. 38 +/- 3 %CVC(max); P < 0.05 compared with predrug). The addition of NLA to losartan reduced POTS and control subject conductances compared with losartan alone (48 +/- 3 vs. 53 +/- 2 %CVC(max)). The data suggest that the reduction in cutaneous NO-dependent vasodilation in low-flow POTS is corrected by AT(1)R blockade.

Estradiol and dihydrotestosterone regulate endothelial cell barrier function after hypergravity-induced alterations in MAPK activity.

Postflight orthostatic intolerance (POI) was reported to be higher in female than male astronauts and may result from sex-dependent differences in endothelial cell (EC) barrier permeability. Here the effect of 17beta-estradiol (E(2)) and dihydrotestosterone (DHT) on the expression of the tight junction protein occludin, EC barrier function, and MAPK activation over time was tested after subjecting human umbilical vein EC (HUVEC) to brief hypergravity identical to that experienced by astronauts during liftoff (LO) into space. After LO hypergravity, HUVEC showed a time-dependent decrease in occludin correlating with an increase in paracellular permeability and a decrease in transendothelial electrical resistance, indicating a decrease in EC barrier function. LO hypergravity inhibited MAPK activation, which remained suppressed 4 h after LO. Inhibition of MAPK activation correlated with decreased phosphotyrosine occludin, decreased cytochrome-c oxidase activity, and increased paracellular permeability, suggesting a mechanism by which LO hypergravity decreased EC barrier function. Time-dependent differences in MAPK activation, decreased occludin, and EC barrier function between HUVEC treated with E(2) vs. DHT were observed. HUVEC showed delayed activation of MAPK with DHT, i.e., 4 h rather than 2 h for E(2), which correlated with decreased paracellular permeability and the observed sex differences in POI in astronauts. These data temporally separate E(2) and DHT effects in HUVEC and provide evidence for the possible protective roles of sex steroids on EC function after brief exposure to low hypergravity.

Acute hypoxemia increases cardiovascular baroreceptor sensitivity in humans.

BACKGROUND: We postulated that acute hypoxemia increases susceptibility to orthostatic hypotension by increasing the sensitivity of cardiovascular baroreceptors. METHODS: Hemodynamics were measured noninvasively in 17 healthy, normotensive subjects while being subjected to decreasing venous return by exposure to lower body negative pressure (LBNP) and breathing either a normobaric normoxic (21% O2) or normobaric hypoxic (12% O2) gas mixture. RESULTS: Hypoxia variably decreased hemoglobin saturation (in percent+/-SEM, from 99%+/-1% to 87%+/-2%, P<.01). Incremental increases in LBNP to -50 mm Hg significantly lowered systolic blood pressure (BP), pulse pressure (PP), forearm blood flow (FBF), and increased heart rate (HR). Hypoxia significantly increased baseline systolic BP, PP, and HR. The maximum change in HR in response to LBNP-induced reductions in PP increased during acute hypoxemia (maximum DeltaHR/DeltaPP, in +/-SEM) from 1.32+/-0.18 beats/min/mm Hg v 1.91+/-0.25 beats/min/mm Hg, P<.05. Those subjects who had the most hemoglobin desaturation during hypoxia, when compared to those subjects who desaturated minimally, had greater systolic BP at rest (128+/-3 mm Hg v 114+/-3 mm Hg, P=.05) and during LBNP (115+/-4 mm Hg v 100+/-1 mm Hg, P=.01). CONCLUSIONS: Acute hypoxia increased compensatory HR responses to LBNP-dependent reductions in BP. Those normotensive individuals with higher BP at rest and during LBNP developed greater degrees of hypoxia-induced hemoglobin desaturation. Patients with sleep apnea with periods of hypoxemia are prone to hypertension; more important, patients with higher BPs also demonstrate greater degrees of hypoxia-induced desaturation of oxyhemoglobin.