Anthony L. Sica

Chronic-intermittent hypoxia: a model of sympathetic activation in the rat

This review focuses upon the development of a small animal model that incorporates exposure to chronic-intermittent hypoxia to produce systemic hypertension similar to that experienced by humans with the obstructive sleep apnea syndrome. It has been suggested that experimentally-induced hypertension, like human hypertension, is due to activation of the sympathetic nervous system. That hypothesis is supported by physiological studies carried out in humans with obstructive sleep apnea as well as in animals exposed to chronic-intermittent hypoxia. Furthermore, recent anatomical studies of exposed animals strongly suggested that activation was widespread and included cortical and brainstem components of the sympathetic system. Such findings, while illustrating the complexity of modeling human disease in animals, also demonstrate the heuristic value of chronic-intermittent hypoxia as an experimental approach.

Expression of c-fos in the rat brainstem after chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) may cause sustained systemic hypertension by increasing sympathetic neural discharge (SND). We hypothesized that CIH alters brainstem circuits modulating SND. After 30 days of CIH exposure in rats, increased c-fos labeling was seen in the nucleus of the solitary tract and ventrolateral medulla as well as other brainstem regions involved in regulation of SND. Increased expression of c-fos after CIH may indicate changes in neuronal genetic transcription which ultimately modulate SND.

High-frequency and medium-frequency components of different inspiratory nerve discharges and their modification by various inputs.

In decerebrate paralyzed cats, spectral analysis was performed on simultaneous recordings of efferent inspiratory nerves (phrenic, recurrent laryngeal, hypoglossal). Spectral peaks were present both in the high-frequency (HFO) range (50-100 Hz) and the medium-frequency (MFO) range (20-50 Hz). Different activities were coherent only in the HFO range, indicating that the HFOs arise in a common inspiratory pattern generator that drives the different motoneuron populations, whereas the MFOs are specific to different systems.

Hypoglossal motoneuron responses to pulmonary and superior laryngeal afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the inspiratory discharges of the hypoglossal (whole nerve or single fibers), phrenic, and recurrent laryngeal nerves were compared, and the effects of pulmonary and superior laryngeal afferent inputs were observed. During lung inflations in phase with neural inspiration, hypoglossal and recurrent laryngeal activities differed from phrenic with respect to (a) burst onset times: both preceded the phrenic; (b) overall pattern: phrenic, augmenting; hypoglossal, decrementing; recurrent laryngeal, plateau-like. When inflation was withheld, the phrenic pattern was not markedly changed, but both hypoglossal and recurrent laryngeal became augmenting; the marked increase of hypoglossal activity (both whole nerve and single fiber) indicated strong inhibition by lung afferents. Superior laryngeal electrical stimulation evoked excitation of the contralateral phrenic (latency 4.1 msec) and the ipsilateral whole hypoglossal (latency 5.3 msec), followed by bilateral inhibitions (durations 20-30 msec); most hypoglossal fibers showed only inhibition. We conclude that, although both hypoglossal and phrenic outputs are driven by the inspiratory pattern generator(s), their promotor systems differ with respect to influences from central and peripheral inputs.

Chronic-intermittent hypoxia induces immediate early gene expression in the midline thalamus and epithalamus

Chronic-intermittent hypoxia (CIH) was postulated to activate thalamic regions that are synaptically related to autonomic-related areas of the cerebral cortex. Animals exposed to CIH for 30 days exhibited c-fos labeling in paraventricular thalamic and lateral habenular nuclei. Our findings strongly suggest activation of a diencephalic network that participates in behavioral responses to chronic stress.

Immediate-early gene expression in cerebral cortex following exposure to chronic-intermittent hypoxia

Chronic-intermittent hypoxia (CIH) was postulated to evoke c-fos expression in cortical regions that modulate sympathetic discharge. Animals exposed to CIH for 30 days exhibited c-fos labeling in medial prefrontal, cingulate, retrosplenial, and insular cortices. Our findings strongly suggest activation of cortical circuits that adaptively regulate sympathetic and cardiovascular activities.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is prevalent with type 2 diabetes. Conversely, nondiabetic patients with OSA are at increased risk of developing insulin resistance and diabetes. These disorders independently contribute to increased cardiovascular and cerebrovascular morbidity and mortality. The pathophysiology of OSA may help explain these associations. Evidence demonstrates that treatment of OSA with continuous positive airway pressure may lead to improvement in insulin sensitivity, hemoglobin A1c, systemic hypertension, and other components of the metabolic syndrome. Recognizing and treating OSA in patients with insulin resistance or diabetes ameliorates OSA-related symptoms and improves cardiometabolic risk.

Power spectral analyses of inspiratory activities in neonatal pigs.

In anesthetized neonatal pigs, spectral analyses were done for inspiratory nerve and neuronal activities. Peaks in power spectra of phrenic roots were observed at high frequencies and at medium frequencies. In contrast, peaks in recurrent laryngeal and hypoglossal nerve spectra were found only at medium frequencies. Significant coherence estimates were obtained only at medium frequencies, indicating that different motoneuron pools share inputs from a common neural oscillator.

The area postrema of newborn swine is activated by hypercapnia : relevance to sudden infant death syndrome?

This study was performed to investigate a role of the neonatal area postrema (AP) in the chemoreceptor response to hypercapnia which is defective in sudden infant death syndrome (SIDS). AP responses to CO2 inhalation were monitored in 1 to 5 week old piglets by mapping neurons that were induced to express the c-fos gene product, Fos--a marker of functional activation. Interpretive confounds were minimized by controlling for hypoxia, the effects of surgical procedures and ambient environmental stressors on neuronal activity (c-fos expression). The AP demonstrated a powerful and reproducible response in neonatal swine breathing 10% CO2 for 1 h. Intensely immunolabeled nuclei were detected throughout the longitudinal extent of the circumventricular organ, and were especially heavily concentrated at rostral levels proximal to obex. Quantitative analysis verified statistically significant increases in numbers of cells that were induced to express Fos-like immunoreactivity (FLI) in the AP of CO2- stimulated piglets as compared to control groups. No detectable age-related differences were observed in AP response patterns. Conclusions. The AP responds to hypercapnic stress in the newborn piglet. A mature circumventricular organ response in the neonate may be crucial in defending against common environmental stressors, such as nicotine exposure--an emetic agent acting via the AP and a major risk factor in SIDS. Hence, a defect of the AP or its network may underlie a loss of state-dependent controls over cardiopulmonary reflex function in SIDS.

CO2-induced expression of c-fos in the nucleus of the solitary tract and the area postrema of developing swine

This investigation was performed to determine whether hypercapnic exposure elicited expression of the c-fos protooncogene product, FOS, in nucleus of the solitary tract (NTS) and area postrema (AP) neurons of developing swine. Mean arterial blood pressure (MAP) and heart rate (HR) were also monitored to evaluate whether numbers of neurons containing FOS were related to changes of MAP and HR. In each experiment, two litter-matched piglets were prepared simultaneously, i.e., Saffan anesthesia, paralysis, and artificial ventilation (100% O(2)). One animal was exposed to hypercapnia (1 h of 10% CO(2), balance oxygen), while the other continued to breathe 100% O(2). Animals were studied at three different ages: 5-8 days, 13-15 days, and 26-34 days old. In the NTS, FOS expression was prominent in regions corresponding to the general visceral afferent subdivision; the AP showed no such topographic distribution. The number of NTS and AP neurons with FOS in hypercapnic-exposed animals was significantly greater than those of unexposed animals. However, an age-related increase of FOS was observed only for NTS neurons, with the greatest number observed in 13- to 15-day-old animals. Increases of MAP, not HR, were noted during the early part of hypercapnia in the 5- to 8-day-old group; older animals exhibited no change of MAP. Our findings demonstrated that prolonged hypercapnic stimulation elicited FOS expression in AP and NTS neurons of developing animals, and that such expression was non-uniform, depending upon the region studied.