Effects of Central Muscarinic-1 Receptor Stimulation on Blood Pressure Regulation

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Abstract
Stimulation of central nervous system muscarinic-1 (M1) receptors in animals increases blood pressure, heart rate, and sympathetic outflow. In Alzheimer's disease, stimulation of central M1 receptors is reduced. When the oral formulation of the selective M1 agonist xanomeline was tested for the treatment of Alzheimer's disease, an increased incidence of syncope was observed. Therefore, we used Alzheimer's disease as a model of relative M1 deficiency to determine the effect of M1 receptor stimulation on blood pressure regulation in humans. Eight Alzheimer's patients and 6 healthy age- and sex-matched subjects underwent blood pressure, heart rate, forearm vascular resistance, plasma norepinephrine, and heart rate variability measurements during 90 minutes after ingestion of xanomeline or placebo, then during 45 minutes of head-up tilt. Alzheimer's patients were studied on three occasions: after placebo, the first dose of xanomeline, and 3 days of xanomeline. Normal subjects were studied after placebo and the first dose of xanomeline. A subset of 5 Alzheimer's patients was studied with the peripheral muscarinic antagonist methscopolamine. Oral xanomeline increased supine systolic and diastolic blood pressures in normal subjects and heart rate and plasma norepinephrine in all subjects. During the placebo tilt, 0 of 8 Alzheimer's patients and 2 of 6 healthy subjects developed near-syncope, and during the first-dose xanomeline tilt, 4 of 8 Alzheimer's patients and 3 of 6 healthy subjects had near-syncope. The maximal decrease in systolic blood pressure during tilt was greater with xanomeline than placebo in both groups (P<.03). Methscopolamine did not prevent xanomeline-induced hypotension. Central M1 receptor stimulation with the oral formulation of xanomeline in humans is associated with sympathetic stimulation under supine conditions and impaired baroreflex compensation during tilt. Alzheimer's patients, who presumably lack M1 receptor activity, may have a reduced risk of tilt-induced syncope compared with normal subjects. Both groups, however, have enhanced susceptibility to hypotension and syncope when M1 receptor activity is pharmacologically increased.