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Propofol may vary heart rate by modulating GABAergic neurotransmission to cardiac parasympathetic neurons. At clinically relevant concentrations (> or =1.0 microm), propofol facilitated GABAergic responses in cardiac vagal neurons by increasing decay time, which would increase inhibition of cardioinhibitory cardiac vagal neurons and evoke an increase in heart rate. At higher supraclinical concentrations (> or =50 microm), propofol inhibits GABAergic neurotransmission to cardiac vagal neurons, which would evoke a decrease in heart rate.

Maternal cigarette smoking and prenatal nicotine exposure increase the risk for sudden infant death syndrome (SIDS) by 2-to 4-fold, yet despite adverse publicity, nearly one of four pregnant women smoke tobacco. Infants who succumb to SIDS typically experience a severe bradycardia that precedes or is accompanied by centrally mediated life-threatening apneas and gasping. Although the causes of the apnea and bradycardia prevalent in SIDS victims are unknown, it has been hypothesized that these fatal events are exaggerated cardiorespiratory responses to hypoxia or hypercapnia. Changes in heart rate are primarily determined by the activity of cardiac vagal neurons (CVNs) in the brainstem. In this study, we tested whether hypoxia/hypercapnia evokes synaptic pathways to CVNs and whether these cardiorespiratory interactions are altered by prenatal exposure to nicotine. Spontaneous rhythmic inspiratoryrelated activity was recorded from the hypoglossal rootlet of 700-to 800-m medullary sections. CVNs were identified in this preparation by retrograde fluorescent labeling, and excitatory synaptic inputs to CVNs were isolated and studied using patchclamp electrophysiologic techniques. Hypoxia/hypercapnia did not elicit an increase in excitatory neurotransmission to CVNs in unexposed animals, but in animals that were exposed to nicotine in the prenatal period, hypoxia/hypercapnia recruited an excitatory neurotransmission to CVNs. This study establishes a likely neurochemical mechanism for the exaggerated decrease in heart rate in response to hypoxia/hypercapnia that occurs in SIDS victims. There are at least two major physiologic interactions between the respiratory system and the neural control of heart rate. The most ubiquitous cardiorespiratory interaction is respiratory sinus arrhythmia. During each respiratory cycle, the heart beat slows during postinspiration/expiration, and heart rate increases during inspiration. Such increases in heart rate during inspiration are observed in a wide variety of mammals, including both neonatal (1) and adult humans (2) and rats (3). Respiratory sinus arrhythmia helps match pulmonary blood flow to lung inflation and maintain the appropriate diffusion gradient for oxygen in the lungs (4).Although feedback from pulmonary stretch receptors, direct respiratory related-changes in venous return, and cardiac stretch can evoke respiratory-related fluctuations in heart rate, the dominant source of respiratory sinus arrhythmia originates from the brainstem (4,5). Respiratory sinus arrhythmia persists when the lungs are stationary (caused by muscle paralysis or constant flow ventilation), and the respiratory modulation of heart rate remains synchronized with brainstem respiratory rhythms even when artificial ventilation of the lungs and chemoreceptor activation occur at different intervals (6,7). In animals, including humans, respiratory sinus arrhythmia is mediated via cardiac vagal activity. Respiratory sinus arrhythmia persists in experimental animals upon sectioning sympathetic pathways and in...

Hypercapnia evokes a strong cardiorespiratory response including gasping and a pronounced bradycardia; however, the mechanism responsible for these survival responses initiated in the brainstem is unknown. To examine the effects of hypercapnia on the central cardiorespiratory network, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and inhibitory synaptic neurotransmission to cardioinhibitory vagal neurons (CVNs). Hypercapnia differentially modulated inhibitory neurotransmission to CVNs; whereas hypercapnia selectively depressed spontaneous glycinergic IPSCs in CVNs without altering respiratory-related increases in glycinergic neurotransmission, it decreased both spontaneous and inspiratory-associated GABAergic IPSCs. Because maternal smoking is the highest risk factor for sudden infant death syndrome (SIDS) and prenatal nicotine exposure is proposed to be the link between maternal smoking and SIDS, we examined the cardiorespiratory responses to hypercapnia in animals exposed to nicotine in the prenatal and perinatal period. In animals exposed to prenatal nicotine, hypercapnia evoked an exaggerated depression of GABAergic IPSCs in CVNs with no significant change in glycinergic neurotransmission. Hypercapnia altered inhibitory neurotransmission to CVNs at both presynaptic and postsynaptic sites. Although the results obtained in this study in vitro cannot be extrapolated with certainty to in vivo responses, the results of this study provide a likely neurochemical mechanism for hypercapnia-evoked bradycardia and the dysregulation of this response with exposure to prenatal nicotine, creating a higher risk for SIDS.

nicotine exposure alters the types of nicotinic receptors that facilitate excitatory inputs to cardiac vagal neurons. J Neurophysiol 92: 2548 -2554, 2004. First published June 22, 2004 10.1152/jn.00500.2004. Nicotinic receptors play an important role in modulating the activity of parasympathetic cardiac vagal neurons in the medulla. Previous work has shown nicotine acts via at least three mechanisms to excite brain stem premotor cardiac vagal neurons. Nicotine evokes a direct increase in holding current and facilitates both the frequency and amplitude of glutamatergic neurotransmission to cardiac vagal neurons. This study tests whether these nicotinic receptor-mediated responses are endogenously active, whether ␣4␤2 and ␣7 nicotinic receptors are involved, and whether prenatal exposure to nicotine alters the magnitude of these responses and the types of nicotinic receptors involved. Application of neostigmine (10 M) significantly increased the holding current, amplitude, and frequency of miniature excitatory postsynaptic current (mEPSC) glutamatergic events in cardiac vagal neurons. In unexposed animals, the nicotine-evoked facilitation of mEPSC frequency, but not mEPSC amplitude or holding current, was blocked by ␣-bungarotoxin (100 nM). Prenatal nicotine exposure significantly exaggerated and altered the types of nicotinic receptors involved in these responses. In prenatal nicotine-exposed animals, ␣-bungarotoxin only partially reduced the increase in mEPSC frequency. In addition, in prenatal nicotine-exposed animals, the increase in holding current was partially dependent on ␣-7 subunit-containing nicotinic receptors, in contrast to unexposed animals in which ␣-bungarotoxin had no effect. These results indicate prenatal nicotine exposure, one of the highest risk factors for sudden infant death syndrome (SIDS), exaggerates the responses and changes the types of nicotinic receptors involved in exciting premotor cardiac vagal neurons. These alterations could be responsible for the pronounced bradycardia that occurs during apnea in SIDS victims.