Endogenous circulating sympatholytic factor in orthostatic intolerance

Sympathotonic orthostatic hypotension (SOH) is an idiopathic syndrome chara cterized by tachycardia, hypotension, elevated plasma norepinephrine, and s ymptoms of orthostatic intolerance provoked by assumption of an upright pos ture. We studied a woman with severe progressive SOH with blood pressure un responsive to the presser effects of alpha (1)-adrenergic receptor (AR) ago nists, We tested the hypothesis that a circulating factor in this patient i nterferes with vascular adrenergic neurotransmission. Preincubation of porc ine pulmonary artery vessel rings with patient plasma produced a dose-depen dent inhibition of vasoconstriction to phenylephrine in vitro, abolished va soconstriction to direct electrical stimulation, and had no effect on nonad renergic vasoconstrictive stimuli (endothelin-1), PGF-2 alpha (or KCl), Pre incubation of vessels with control plasma was devoid of these effects. SOH plasma inhibited the binding of an alpha (1)-selective antagonist radioliga nd ([I-125]HEAT) to membrane fractions derived from porcine pulmonary arter y vessel rings, rat liver, and cell lines selectively overexpressing human ARs of the alpha (1B) subtype but not other AR subtypes (alpha (1A) and alp ha (1D)), We conclude that a factor in SOH plasma can selectively and irrev ersibly inhibit adrenergic ligand binding to alpha (1B) ARs, We propose tha t this factor contributes to a novel pathogenesis for SOH in this patient. This patient's syndrome represents a new disease entity, and her plasma may provide a unique tool for probing the selective functions of alpha (1)-ARs .