ABSTRACT
Atomoxetine is a central norepinephrine reuptake inhibitor used to treat attention deficit hyperactivity disorder. We tested the effects of atomoxetine upon the heart rate (HR) and mean arterial blood pressure (mBP) response to aversive conditioning. In Protocol 1 the mBP and HR responses to a stress (15s tone followed by shock) were tested in 8 Sprague-Dawley rats given saline pretreatment for 3 days; the rats' responses were then tested for 3 additional days following atomoxetine (1mg/kg, sc). Atomoxetine decreased (p<0.05) baseline mBP from 128+/-11 mm Hg (mean+/-SD) to 117+/-19 mm Hg; baseline HR slowed from 380+/-23 bpm to 351+/-21 bpm. The mBP increase to acute stress was similar after saline vs. after drug, but the peak was attained more slowly. After atomoxetine HR tended to slow during stress rather than accelerate. In Protocol 2 the cardiovascular responses were tested (n=6) for 3 days post-saline and for 3 days after a higher dose of atomoxetine (2mg/kg, sc). The average HR acceleration during the last 10s of the stress after saline (+7.5+/-14.7 bpm) was replaced by a HR slowing (-6.2+/-10.5 bpm). We conclude that drug treatment (a) decreases baseline sympathetic tone and/or elevates cardiac parasympathetic tone; (b) slows sympathetic arousal to acute stress without changing its magnitude; and, (c) enables the emergence of elevated parasympathetic tone during the stress. These autonomic consequences are consistent with atomoxetine's anxiolytic and transient sedative effects.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Autonomic Nervous System/drug effects , Bradycardia/drug therapy , Heart Rate/drug effects , Propylamines/pharmacology , Tachycardia/drug therapy , Adrenergic Uptake Inhibitors/therapeutic use , Analysis of Variance , Animals , Atomoxetine Hydrochloride , Blood Pressure/drug effects , Blood Pressure/physiology , Bradycardia/etiology , Conditioning, Classical/physiology , Disease Models, Animal , Heart Rate/physiology , Propylamines/therapeutic use , Rats , Rats, Sprague-Dawley , Stress, Psychological/complications , Stress, Psychological/etiology , Tachycardia/etiologyABSTRACT
We compared arterial blood pressure (BP) and heart rate (HR) control in 9- to 11-week old obese Zucker rats (n=10; weight=452+/-45 g, average+/-SD) to age-matched, lean Zucker animals (n=13; weight=280+/-46 g). BP was measured by indwelling catheter. Baseline pressure was 113.1+/-7.0 mm Hg in the lean vs. 111.7+/-5.6 in the obese rats (NS). Baseline HR was 413+/-43 in the lean vs. 422+/-22 bpm in the obese animals (NS). Rats were classically conditioned by following a 15-second tone (CS+) with a 0.5-second tail shock. There were no between-group differences in the BP response to CS+. Conversely, heart rate (HR) decreased significantly (p<0.05) more during the last 10 s of the tone in the lean group (-46.0+/-21.5 bpm) vs. the obese (-17.8+/-21.7 bpm). This bradycardia was blocked by atropine. Finally, the change in HR divided by the change in arterial BP (DeltaHR/DeltaBP) following an intravenous bolus of phenylephrine (PE; 5 microg/kg) and following sodium nitroprusside (NP; 5 microg/kg) was determined. The DeltaHR/DeltaBP following PE was smaller in the obese (n=6; -1.36+/-0.60) vs. lean (n=5; -2.80+/-0.92); there was no difference in the response following NP. These data indicate that the BP response to a behavioral challenge did not differ in the obese rat vs. the lean animal, but that the obese subjects had an attenuated parasympathetic response to the stress, probably secondary to alterations in baroreflex function.
