Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an autoimmune orthostatic hypotension

Background: Orthostatic hypotension (OH) is characterized by an abnormal autonomic response to upright posture. Activating autoantibodies to beta 1/2-adrenergic (AA beta 1/2AR) and M2/3 muscarinic receptors (AAM2/3R) produce vasodilative changes in the vasculature that may contribute to OH. Methods: Immunoglobulin (Ig)G from 6 patients with idiopathic OH harboring autoantibodies and from 10 healthy control subjects were examined for: 1) beta 1AR and M2R activity with a perfused Purkinje fiber assay and PKA assay in H9c2 cells and 2) vasodilator beta 2AR and M3R activity using a pressurized cremaster resistance arteriole assay. Changes in IgG activity with and without propranolol, atropine, and L-NAME were used to estimate AA beta AR, AAM2R, and AAM3R activation of their respective functions. Results: All six patients had elevated enzyme-linked immunosorbent assay titers to at least one of the receptors compared with controls. beta AR-mediated contractility activity and M2R activity were increased in five of the six patients. IgG from all six patients produced a direct vasodilator effect on cremaster arterioles. beta AR and nitric oxide synthase blockade led to near normalization of IgG-induced vasodilation. Conclusion: AA beta 1/2AR and AAM2/3R are present in some patients with idiopathic OH compatible with an in vivo effect. These autoantibodies and their cardiovascular effects provide new mechanistic insights into the pathophysiology of OH. J Am Soc Hypertens 2012;6(1):40-47. Published by Elsevier Inc on behalf of American Society of Hypertension.