Distribution of carotid body chemoreceptor afferents in the medulla of the cat

Abdominal muscles serve many roles; in addition to breathing, especially at higher levels of chemical drive or at increased end-expiratory lung volumes, they are responsible for, or contribute to, such protective reflexes as cough, sneeze, and vomiting, generate the high intra-abdominal pressures necessary for defecation and parturition, are active during postural adjustments, and play an essential role in vocalization in many species. Despite this widespread involvement, however, their control has, with rare exceptions, received little attention for two major reasons.

First, in most anesthetized or decerebrate preparations, they are relatively inactive at rest, in part because the position of the preparation (supine or prone with abdomen supported), reduces lung volume and, therefore, their activity.

Second, unlike phrenic motoneurons innervating the diaphragm, identification of motoneurons to a particular abdominal muscle is difficult.

At the lumbar level, a given motoneuron may innervate any one of the four abdominal muscles; at the thoracic level, they are also intermixed with those innervating the intercostals.

The two internal muscles, the internal oblique and the transverse abdominis, respond more to increases in chemical or volume-related drive than the two external muscles, the rectus abdominis and external oblique; the basis for this differential sensitivity is unknown.

Segmental reflexes at the thoracic and lumbar levels are sufficient to activate abdominal motoneurons in the absence of descending drive but the basis for these reflex effects is also unknown.

Neuroanatomical experiments demonstrate many more inputs to, and outputs from, the nucleus retroambigualis, the brainstem region in which the premotor neurons are located, than can be accounted for by their respiratory role alone. These other connections likely subserve activities other than respiration.

Studies of the multifunctional roles of the abdominal muscles, on the basis of recent work, hold considerable promise for improving our understanding of their control.

2-Amino-5-phosphonovalerate (AP5; 153 pmol) injected into the rostral ventrolateral medulla (RVLM) inhibited pressor responses induced by carotid chemoreceptor stimulation. AP5 also inhibited pressor responses to aspartate (0.75 nmol) but not to glutamate (0.53 nmol) similarly injected. High K⁺ (50 mM) released endogenous aspartate and glutamate in a Ca²⁺-dependent manner from the RVLM. Chemoreceptor stimulation caused a release of aspartate but not of glutamate in the RVLM, and sinus nerve denervation abolished the release of aspartate. Increases in blood pressure induced by intravenous phenylephrine did not release aspartate. These results support the hypothesis that endogenous aspartate in the rat RVLM is involved in the mediation of chemoreceptor reflexes.

The past decade has witnessed rapid progress in defining neural circuits and mechanisms in the brain, responsible for regulation of the sympathetic nerve activity and cardiovascular functions. Several groups of cardiovascular neurons in the brainstem form the fundamental neural circuits, through which reflexly and centrally initiated sympathetic responses are processed. Their interplay determines the levels of sympathetic nerve activity and vascular tone. Substantial evidence indicates that a small population of reticulospinal vasomotor neurons in the rostroventrolateral reticular nucleus of the medulla oblongata play critical and integrative roles by: 1) providing, largely by their intrinsic pacemaker activity, tonic sympathoexcitation, thus maintaining normal blood pressure and organ blood flows, 2) mediating a variety of circulatory reflexes and centrally initiated sympathetic responses thereby helping to match organ blood flow to metabolic demands, and 3) acting as intrinsic oxygen detectors which orchestrate appropriate autonomic response programs to protect the integrity of brain in response to acute hypoxia-ischemia. Elaboration of the neural mechanisms and cellular and molecular properties of these vasomotor neurons related to dynamic regulation of the cardiovascular system in normal and disease states will be of relevance to a full appreciation of their role in adaptation of the organism to its internal and external environments and to the development of strategies to fight against neurogenic cardiovascular diseases and to restore normal functions.

The sites of origin and termination of efferent and afferent fibers in the carotid sinus nerve (CSN) were investigated in the Japanese monkey. After application of a mixture of horseradish peroxidase (HRP) and wheat germ aggulutinin-conjugated HRP to the central cut end of the CNS, sensory ganglion neurons were labeled inthe jugular ganglion of the vagus nerve, as well as in the superior and petrosal ganglia of the glossopharyngeal nerve. Many sympathetic ganglion neurons were also labeled retrogradely in the superior cervical ganglion. In the brain, many labeled terminals were seen ipsilaterally in the lateral division of the nucleus of the solitary tract (NST). A few neuronal cell bodies were also labeled ipsilaterally in a reticular region dorsomedial to the caudal one-third of the facial nucleus. The results indicate that the CSN of the Japanese monkey is composed mainly of afferent fibers terminating in the NST, that the afferent fibers in the CSN originate not only from the superior and petrosal ganglia of the glossopharyngeal nerve but also from the jugular ganglion of the vagus nerve, and that efferent fibers contained in the CSN arise from the medullary reticular formation and superior cervical ganglion.

The localization and brain stem projections of neurons innervating the carotid sinus of the dog were studied by horseradish peroxidase histochemistry following microinjection of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) under the adventitia of the carotid sinus. Within the brain stem, labeled afferent fibers and presumptive terminals were found bilaterally in the caudal nucleus tractus solitarius (nTS), the area postrema (AP), and the lateral tegmental field (LTF), reaching the area of the nucleus ambiguus (nA). Sparse labeling was also seen in the ipsilateral spinal trigeminal nucleus (SpV) and lateral cuneatus nucleus (LCn). These findings suggest the existence of multiple pathways by which peripheral baroreceptor inputs may influence central cardiovascular-related neurons. In addition to classically defined relay in the nTS, carotid sinus afferents may also interact more directly with these neurons in other brain stem regions.

The carotid body chemoreceptor afferents have been reported to project to a discrete area located in the nucleus commissuralis of nucleus tractus solitarius [A. Vardhan et al., Am. J. Physiol., 264 (1993) R41–R50]. The afore-mentioned study was done in spontaneously breathing rats and the afferents and efferents located in the chest wall and the respiratory tract of these animals were intact. In order to exclude the role, if any, of these afferents and efferents, in the present experiments respiratory changes were monitored by recording the phrenic nerve activity instead of tracheal airflow. Experiments were carried out in pentobarbital-anesthesized, bilaterally vagotomized, paralyzed and aartificially ventilated rats with a pneumothorax. The carotid body chemoreceptors were stimulated with tracheal administration of nitrogen for 7–10 s. The chemoreceptor stimulation induced an increase in the frequency and amplitude of phrenic nerve bursts. A decrease in the duration of inspiratory (T_I) expiratory (T_E) and total cycles (T_TOT) was observed in the phrenic nerve activity. Inhibition of neuronal cell bodies by microinjections of muscimol (140 pmol/20 nl) into a discrete area in the commissural subnucleus of the nucleus tractus solitarius (coordinates in mm: 0.3 rostral to 0.5 caudal, 0 to 0.5 lateral and 0.3 to 0.5 deep with respect to the calamus scriptorius), attenuated the phrenic nerve responses to the carotid body stimulation. On the other hand, control injections of saline (0.9%) into this site did not alter the phrenic nerve responses to the carotid body stimulation. Microinjections of bicuculline methiodide (a GABA_A receptor antagonist) reversed the actions of muscimol. These results further confirm that the carotid body chemoreceptors project to a discrete are in the commissural subnucleus of the nucleus tractus solitarius. This site is tentatively called chemoreceptor projection site (CPS).