http://www.ncbi.nlm.nih.gov/pubmed/22215709 Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. Li H, Kem DC, Reim S, Khan M, Vanderlinde-Wood M, Zillner C, Collier D, Liles C, Hill MA, Cunningham MW, Aston CE, Yu X. Source Endocrinology and the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, TCH 6E103, 1200 Everett Dr, Oklahoma City, OK 73104. Abstract Agonistic autoantibodies to the ?-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to ?2-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 ?2 receptor activation and ?-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of ?2 and M3 receptors in the patient group compared with controls. A dose response was observed for both IgG activation of ?2 and M3 receptors and inhibition of their activation with the nonselective ? blocker propranolol and muscarinic blocker atropine. The antibody effects on ?2 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 ?2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the ?-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 57.710.4 to 35.34.6 and 24.35.8, respectively; P<0.01; n=3), indicating that antibody activation of vascular ?2 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.