Adrenergic cardiovascular control before and after removal of stimulatory α-1 adrenoreceptor antibodies.

Adrenergic Cardiovascular Control Before and After Removal of Stimulatory -1 Adrenoreceptor Antibodies To the Editor: Agonistic autoantibodies directed against G protein–coupled receptors are implicated in the pathogenesis of various human cardiovascular disorders. A patient subset with idiopathic dilated cardiomyopathy features agonistic antibodies directed against -1 adrenoreceptors. Subsequently, immunization against -adrenoreceptors in rats, as well as transfer of serum to nonimmunized animals, induces left ventricular dilation and dysfunction.1 Agonistic antibodies against the angiotensin II subtype 1 receptor may contribute to preeclampsia and humorally mediated kidney transplant rejection. More recent studies identified agonistic antibodies against the -1 adrenoreceptor in 51% of treatmentresistant hypertension patients.2 In vitro, patient and rabbit -1 adrenoreceptor antibodies activated protein kinase Cand transient extracellular-related kinase phosphorylation and induced mesentery artery segment contraction.2 Finally, 5 patients in whom agonistic -1 adrenoreceptor antibodies were removed through immunoabsorption showed favorable blood pressure responses.2 Another study arrived at similar conclusions after infused antibodies rapidly raised blood pressure in anesthetized rats; prazosin abolished the response.3 However, how agonistic -1 adrenoreceptor antibodies might affect cardiovascular adrenergic regulation in humans is unknown. To address this issue, we tested responses to physiological sympathetic nervous system stimuli and exogenous adrenergic agonists before and after immune absorption. We studied 5 patients (4 men and 1 woman; 58 4 years; 31 2 kg/m) with treatment-resistant arterial hypertension and agonistic -1 adrenoreceptor antibodies whose office blood pressure data have been included in a previous report.2 Patients received no antiadrenergic medications. All of the other antihypertensive medications were kept constant throughout the study. Patients underwent immune adsorption on 5 consecutive days. At each session, the calculated plasma volume was passed through adsorption columns at 50 mL/min. Levels of antibodies against the 1-adrenergic receptor were measured by a bioassay using spontaneously beating rat cardiomyocytes. Immune adsorption substantially reduced -1 adrenoreceptor autoantibodies (24 1 bpm/min before versus 5 1 bpm/min after immune adsorption; P 0.001). Before and 5 to 12 days after immune adsorption, we conducted a battery of autonomic function tests and sensitivity testing with incremental intravenous phenylephrine and nitroprusside doses. ECG and beat-by-beat finger blood pressure (Finapres) were continuously recorded. Brachial blood pressure was monitored to assess absolute blood pressure levels (Dinamap). The local ethics committee approved the study, and written-informed consent was obtained. All data are expressed as mean SEM. Before immune absorption, supine blood pressure was 169 12/88 7 mm Hg, 58 6 bpm. After completion of the immune adsorption protocol, blood pressure was reduced in 4 patients and increased in 1 patient (group average: 146 11/ 78 3 mm Hg; P 0.095/0.238). Resting heart rate was 59 5 bpm before immune adsorption and 59 4 bpm after immune adsorption. Before and after immune adsorption, blood pressure and heart rate responded normally to graded head-up tilt testing. Chronic vascular adrenoreceptor stimulation should decrease adrenergic responsiveness through receptor occupancy and/or desensitization. Yet, with handgrip testing, systolic blood pressure increased 33 10 mm Hg before and 37 4 mm Hg after immune absorption (not significant). With cold pressor testing, systolic blood pressure increased 18 9 mm Hg before and 14 4 mm Hg after immune absorption (not significant). Nitroprusside elicits baroreflex-mediated vascular -adrenoreceptor activation restraining the hypotension.4 The depressor response to nitroprusside was identical before and after immune absorption (Figure). Finally, the pressor response to direct -adrenoreceptor stimulation with phenylephrine was within a normal range and unaffected by immune absorption (Figure). Phenylephrine and nitroprusside-induced heart rate responses were identical 0.0 0.1 0.2