Adrenergic Autoantibody-Induced Postural Tachycardia Syndrome in Rabbits.

Background-Previous studies have demonstrated that functional autoantibodies to adrenergic receptors may be involved in the pathogenesis of postural tachycardia syndrome. The objective of this study was to examine the impact of these autoantibodies on cardiovascular responses to postural changes and adrenergic orthosteric ligand infusions in immunized rabbits. Methods and Results-Eight New Zealand white rabbits were coimmunized with peptides from the alpha 1-adrenergic receptor and beta 1-adrenergic receptor (alpha 1AR). Tilt test and separate adrenergic agonist infusion studies were performed on conscious animals before and after immunization and subsequent treatment with epitope-mimetic peptide inhibitors. At 6 weeks after immunization, there was a greater percent increase in heart rate upon tilting compared with preimmune baseline. No significant difference in blood pressure response to tilting was observed. The heart rate response to infusion of the beta-adrenoceptor agonist isoproterenol was significantly enhanced in immunized animals, suggesting a positive allosteric effect of alpha 1AR antibodies. In contrast, the blood pressure response to infusion of the alpha 1-adrenergic receptor agonist phenylephrine was attenuated in immunized animals, indicating a negative allosteric effect of alpha 1-adrenergic receptor antibodies. Injections of antibody-neutralizing peptides suppressed the postural tachycardia and reversed the altered heart rate and blood pressure responses to orthosteric ligand infusions in immunized animals at 6 and 30 weeks. Antibody production and suppression were confirmed with in vitro bioassays. Conclusions-The differential allosteric effect of alpha 1-adrenergic receptor and alpha 1AR autoantibodies would lead to a hyperadrenergic state and overstimulation of cardiac alpha 1AR. These data support evidence for an autoimmune basis for postural tachycardia syndrome.