Defects in Cutaneous Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7) Production in Postural Tachycardia Syndrome

Stewart, Julian M.; Ocon, Anthony J.; Clarke, Debbie; Taneja, Indu; Medow, Marvin S.

doi:10.1161/hypertensionaha.108.127357

Cited by 54 publications

(46 citation statements)

References 46 publications

(46 reference statements)

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“…This is difficult to accomplish in humans although attempts are underway. Our past data indicate ANG II excess (40,43) and decreased NO bioavailability (41) in LFP, consistent with literature (11,14) in which ANG II induced superoxide overproduction scavenges NO producing peroxynitrite that in turn decreases BH4 further reducing NO formation via NOS uncoupling (15).…”

Section: Limitationssupporting

confidence: 91%

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Ascorbate improves circulation in postural tachycardia syndrome

Stewart

Ocon

Medow

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Stewart JM, Ocon AJ, Medow MS. Ascorbate improves circulation in postural tachycardia syndrome. Am J Physiol Heart Circ Physiol 301: H1033-H1042, 2011. First published May 27, 2011 doi:10.1152/ajpheart.00018.2011.-Low flow postural tachycardia syndrome (LFP) is associated with vasoconstriction, reduced cardiac output, increased plasma angiotensin II, reduced bioavailable nitric oxide (NO), and oxidative stress. We tested whether ascorbate would improve cutaneous NO and reduce vasoconstriction when delivered systemically. We used local cutaneous heating to 42°C and laser Doppler flowmetry to assess NO-dependent conductance (%CVCmax) to sodium ascorbate and the systemic hemodynamic response to ascorbic acid in 11 LFP patients and in 8 control subjects (aged 23 Ϯ 2 yr). We perfused intradermal microdialysis catheters with sodium ascorbate (10 mM) or Ringer solution. Predrug heat response was reduced in LFP, particularly the NO-dependent plateau phase (56 Ϯ 6 vs. 88 Ϯ 7%CVCmax). Ascorbate increased baseline skin flow in LFP and control subjects and increased the LFP plateau response (82 Ϯ 6 vs. 92 Ϯ 6 control). Systemic infusion experiments used Finometer and ModelFlow to estimate relative cardiac index (CI) and forearm and calf venous occlusion plethysmography to estimate blood flows, peripheral arterial and venous resistances, and capacitance before and after infusing ascorbic acid. CI increased 40% after ascorbate as did peripheral flows. Peripheral resistances were increased (nearly double control) and decreased by nearly 50% after ascorbate. Calf capacitance and venous resistance were decreased compared with control but normalized with ascorbate. These data provide experimental support for the concept that oxidative stress and reduced NO possibly contribute to vasoconstriction and venoconstriction of LFP. free radicals; vasoconstriction POSTURAL TACHYCARDIA SYNDROME (POTS) accounts for most cases of chronic orthostatic intolerance (21,28,39,47,48). POTS is defined by excessive increase in upright heart rate and symptoms of orthostatic intolerance (39) improving with recumbence. Our laboratory (42) has described a subset of POTS designated "low flow POTS" (LFP) in which there is marked upright tachycardia and circulatory insufficiency even while supine including resting tachycardia, decreased cardiac output (CO), and decreased regional blood flows with peripheral and cutaneous vasoconstriction, findings often ascribed to a hyperadrenergic state (1, 6). A consistent observation has been increased plasma angiotensin II (ANG II; Refs. 40,43,45), which can act locally to decrease bioavailable nitric oxide (NO) by superoxide scavenging to create peroxynitrite (36). ANG II also acts through reactive oxygen species (ROS; Ref. 35) to increase central and peripheral sympathetic activity (9, 52). Both increased ANG II due to deficient ACE2 and decreased bioavailable NO have been demonstrated in LFP during prior experiments using intradermal microdialysis techniques. Experiments made extensive use of the local vasodilator...

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Section: Limitationssupporting

confidence: 91%

“…A consistent observation has been increased plasma angiotensin II (ANG II; Refs. 40,43,45), which can act locally to decrease bioavailable nitric oxide (NO) by superoxide scavenging to create peroxynitrite (36). ANG II also acts through reactive oxygen species (ROS; Ref.…”

mentioning

confidence: 99%

Ascorbate improves circulation in postural tachycardia syndrome

Stewart

Ocon

Medow

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Many patients with POTS have low plasma, red cell, and total blood volumes as assessed using various techniques. [26][27][28] In one study, 28.9% of patients excreted less than 100 mEq/L of sodium in 24 hours, which was interpreted as consistent with a hypovolemic status. 7 In many cases, these patients have low levels of standing plasma renin activity and aldosterone compared with controls.…”

Section: Article Highlightsmentioning

confidence: 99%

“…However, some patients have a low-flow phenotype associated with inappropriately high plasma angiotensin II levels, reflecting reduced estimated angiotensin-converting enzyme 2 activity. 28 Functional gastrointestinal disorders associated with poor water intake due to nausea or excess fluid loss due to diarrhea may result in hypovolemia with secondary orthostatic symptoms and tachycardia. In this case, POTS HUT ϭ head-up tilt; MIBG ϭ meta-iodobenzylguanidine; NE ϭ norepinephrine; POTS ϭ postural tachycardia syndrome; RAA ϭ renin-angiotensin-aldosterone; VGKC ϭ voltage-gated potassium channel; VM ϭ Valsalva maneuver; VO 2max ϭ maximum oxygen consumption.…”

Section: Article Highlightsmentioning

confidence: 99%

Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder

Benarroch

2012

Mayo Clinic Proceedings

308

354

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Postural tachycardia syndrome (POTS) is defined by a heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. POTS manifests with symptoms of cerebral hypoperfusion and excessive sympathoexcitation. The pathophysiology of POTS is heterogeneous and includes impaired sympathetically mediated vasoconstriction, excessive sympathetic drive, volume dysregulation, and deconditioning. POTS is frequently included in the differential diagnosis of chronic unexplained symptoms, such as inappropriate sinus tachycardia, chronic fatigue, chronic dizziness, or unexplained spells in otherwise healthy young individuals. Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity. The aims of evaluation in patients with POTS are to exclude cardiac causes of inappropriate tachycardia; elucidate, if possible, the most likely pathophysiologic basis of postural intolerance; assess for the presence of treatable autonomic neuropathies; exclude endocrine causes of a hyperadrenergic state; evaluate for cardiovascular deconditioning; and determine the contribution of emotional and behavioral factors to the patient's symptoms. Management of POTS includes avoidance of precipitating factors, volume expansion, physical countermaneuvers, exercise training, pharmacotherapy (fludrocortisone, midodrine, ␤-blockers, and/or pyridostigmine), and behavioral-cognitive therapy. A literature search of PubMed for articles published from January 1, 1990, to June 15, 2012, was performed using the following terms (or combination of terms): POTS; postural tachycardia syndrome, orthostatic; orthostatic; syncope; sympathetic; baroreceptors; vestibulosympathetic; hypovolemia; visceral pain; chronic fatigue; deconditioning; headache; Chiari malformation; Ehlers-Danlos; emotion; amygdala; insula; anterior cingulate; periaqueductal gray; fludrocortisone; midodrine; propranolol; ␤-adrenergic; and pyridostigmine. Studies were limited to those published in English. Other articles were identified from bibliographies of the retrieved articles. 1,2 According to current criteria for adults, 3 POTS is defined by a heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt (HUT) in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. These criteria may not be applicable for individuals with low resting heart rate. For individuals aged 12 to 19 years, the required increment is at least 40 beats/min.3 The orthostatic tachycardia may be accompanied by symptoms of cerebral hypoperfusion and sympathetic hyperactivity that are reliev...

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“…Angiotensin-mediated vasodilation is related to ACE2 and Ang-(1–7) [22]. ACE2 plays a critical role in regulating Ang II production by ACE, either by stimulating an alternative pathway for Ang I degradation or by facilitating the degradation of Ang II into Ang-(1–7).…”

Section: Vasodilator Factors/systemsmentioning

confidence: 99%

Antiangiogenic-Induced Hypertension: The Molecular Basis of Signaling Network

Nagai¹,

Sado²,

Naruse³

et al. 2012

Gynecol Obstet Invest

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Problem: Preeclampsia, a pregnancy-related hypertensive disorder, is one of the leading causes of fetal and maternal death globally. Angiogenic factors including vascular endothelial growth factor (VEGF) are involved in the formation of new blood vessels required for placental development and function. The hallmark of preeclampsia is similar to the toxicities related to antiangiogenesis therapy. VEGF inhibitors or antagonists promote vasoconstriction, hypertension and proteinuria. VEGF plays a role in attenuating hypertension and improving kidney damage in an animal model; however, the mechanisms underlying this effect remain poorly defined. The aim of this paper is to summarize recent advances in VEGF-mediated signaling and the target molecules, and provide new insights into treatment strategies for preeclampsia. Method of Study: This article reviews the English-language literature for pathogenesis of preeclampsia based on VEGF signaling and hypertension. Results: VEGF activates downstream signaling molecules, including Ca²⁺/CAMKK, Rac1/NOX, ROS/ERK, Ezrin/Calpain/PI3K/Akt, PLCγ/PKC and Src/HSP90. Among these signalings, important pathways for receptor-triggered intracellular signaling are (1) the PI3K/Akt-dependent, (2) the PLCγ-dependent and (3) the ERK/Egr-1-dependent pathway. VEGF is closely involved in receptor-activated signaling events, leading to eNOS-dependent NO synthesis and eNOS-independent endothelial cell proliferation, respectively, and thus modulates vasoactive function and angiogenic response. Conclusion: This review highlights the potential role of NO in vasodilation, while stress-related ERK activation might act to strengthen angiogenesis, migration and proliferation. We discuss the similarity between preeclampsia and VEGF-targeted therapy-induced hypertension.

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Defects in Cutaneous Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7) Production in Postural Tachycardia Syndrome

Cited by 54 publications

References 46 publications

Ascorbate improves circulation in postural tachycardia syndrome

Ascorbate improves circulation in postural tachycardia syndrome

Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder

Antiangiogenic-Induced Hypertension: The Molecular Basis of Signaling Network

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