Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism.
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.
Oklahoma City Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Hongliang
H
Li
David C
DC
Kem
Sean
S
Reim
Muneer
M
Khan
Megan
M
Vanderlinde-Wood
Caitlin
C
Zillner
Daniel
D
Collier
Campbell
C
Liles
Michael A
MA
Hill
Madeleine W
MW
Cunningham
Christopher E
CE
Aston
Xichun
X
Yu
D000328:Adult; D000368:Aged; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001285:Atropine / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000276:immunology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007024:Hypotension, Orthostatic / Q000453:epidemiology / Q000276:immunology / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001323:Autoantibodies; D007074:Immunoglobulin G; D043587:Receptor, Muscarinic M3; D018343:Receptors, Adrenergic, beta-2; D014665:Vasodilator Agents; D001285:Atropine; D011433:Propranolol