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(Circulation Research. 2003;93:565.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Respiratory Sinus Arrhythmia

Endogenous Activation of Nicotinic Receptors Mediates Respiratory Modulation of Brainstem Cardioinhibitory Parasympathetic Neurons

Robert A. Neff, Jijiang Wang, Sunit Baxi, Cory Evans, David Mendelowitz

From the Department of Pharmacology, The George Washington University, Washington, DC.

Correspondence to Robert A. Neff, Department of Pharmacology, The George Washington University, 2300 Eye St NW, Washington, DC 20037. E-mail phmdxm{at}gwumc.edu

The heart rate increases during inspiration and decreases during expiration. This respiratory sinus arrhythmia (RSA) occurs by modulation of premotor cardioinhibitory parasympathetic neuron (CPN) activity. However, RSA has not been fully characterized in rats, and despite the critical role of CPNs in the generation of RSA, little is known about the mechanisms that mediate this cardiorespiratory interaction. This study demonstrates that RSA in conscious rats is similar to that in other species. The mechanism of RSA was then examined in vitro. Rhythmic inspiratory-related activity was recorded from the hypoglossal rootlet of 700- to 800-µm medullary sections. CPNs were identified by retrograde fluorescent labeling, and neurotransmission to CPNs was examined using patch-clamp electrophysiological techniques. During inspiratory bursts, the frequency of both spontaneous -aminobutyric acidergic (GABAergic) and spontaneous glycinergic synaptic events in CPNs was significantly increased. Focal application of the nicotinic antagonist dihydro-ß-erythroidine in an ₄ß₂-selective concentration (3 µmol/L) abolished the respiratory-evoked increase in GABAergic frequency. In contrast, the increase in glycinergic frequency during inspiration was not altered by nicotinic antagonists. Prenatal nicotine exposure exaggerated the increase in GABAergic frequency during inspiration and enhanced GABAergic synaptic amplitude both between and during inspiratory events. Glycinergic synaptic frequency and amplitude were unchanged by prenatal nicotine exposure. This study establishes a neurochemical link between neurons essential for respiration and CPNs, reveals a functional role for endogenous acetylcholine release and the activation of nicotinic receptors in the generation of RSA, and demonstrates that this cardiorespiratory interaction is exaggerated in rats prenatally exposed to nicotine.

Key Words: nucleus ambiguus • vagal activity • respiratory sinus arrhythmia • prenatal nicotine • sudden infant death syndrome

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