Agonistic Autoantibodies as Vasodilators in Orthostatic Hypotension A New Mechanism

Agonistic autoantibodies to the beta-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to beta 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 beta 2 receptor activation and beta-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of beta 2 and M3 receptors in the patient group compared with controls. A dose response was observed for both IgG activation of beta 2 and M3 receptors and inhibition of their activation with the nonselective beta blocker propranolol and muscarinic blocker atropine. The antibody effects on beta 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 beta 2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the beta-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 beta 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. (Hypertension. 2012; 59[part 2]: 402-408.)