Agonistic Autoantibodies as Vasodilators in Orthostatic Hypotension: A New Mechanism
Open accessAbstract
Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by ELISA in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 of the patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared with controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the nonselective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of NO) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β-blocker propranolol and the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester partially inhibited IgG-induced vasodilation (percentage of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively; P<0.01; n=3), indicating that antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension.
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Recognition that circulating autoantibodies interact with G protein-coupled receptor targets and modify the autonomic system led the group to identify AAb to the β2AR and M3 muscarinic acetylcholine receptor in subjects with idiopathic orthostatic hypotension.
“Recognition that circulating autoantibodies interact with G protein-coupled receptor targets and modify the autonomic system has led our group to identify AAb to the β2AR and M3 muscarinic acetylcholine receptor in a group of subjects with idiopathic orthostatic hypotension.15”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [15]
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- Authors
- Li, H., Kem, D. C., Reim, S., Khan, M., Vanderlinde-Wood, M., Zillner, C., Collier, D., Liles, C., Hill, M. A., Cunningham, M. W., Aston, C. E., & Yu, X.
- Affiliations
- Oklahoma City VA Medical Center (US)
- From the Oklahoma City Veterans Affairs Medical Center (H.L., D.C.K., X.Y.), Harold Hamm Diabetes Center (H.L., D.C.K., S.R., M.K., M.V., C.Z., D.C., C.L., C.E.A., X.Y.) and Heart Rhythm Institute (H.L., D.C.K., X.Y.), University of Oklahoma Health Sciences Center, Oklahoma City, OK; Department of Microbiology and Immunology (M.W.C.), University of Oklahoma Health Sciences Center, Oklahoma City, OK; Department of Medical Pharmacology and Physiology (M.A.H.), Dalton Cardiovascular Research Center,...
- ORCID
- Venue
- Hypertension
- Published
- 2012-02
- Volume
- 59
- Issue
- 2
- Pages
- 402-408
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC3275920
- OpenAlex
- W2127368438
- Cited by
- 51
- References
- 21
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 1 · 2015: 2 · 2014: 7 · 2013: 3 · 2012: 2
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R56HL056267, R01HL056267)
- National Institute of General Medical Sciences (P20GM104934)
- National Center for Research Resources (P20RR024215)
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- agonistic autoantibodies, orthostatic hypotension, beta2-adrenergic receptor, M3 muscarinic receptor, nitric oxide, propranolol, atropine, L-NAME
- MeSH terms
- Adult, Aged, Animals, Arterioles, Atropine, Autoantibodies, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Female, Humans, Hypotension, Orthostatic, Immunoglobulin G, Male, Middle Aged, Propranolol, Vasodilation, Vasodilator Agents, Comorbidity, Rats, Sprague-Dawley, Receptors, Adrenergic, beta-2, Models, Animal, Receptor, Muscarinic M3, Rats
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