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Three types of hypoxia with different levels of carbon dioxide (hypocapnic, isocapnic, and hypercapnic hypoxia) have been called systemic hypoxia. The systemic hypoxic carotid bodies were enlarged several fold, but the degree of enlargement was different for each. The mean short and long axes of hypocapnic and isocapnic hypoxic carotid bodies were 1.6 (short axis) and 1.8-1.9 (long axis) times larger than normoxic control carotid bodies, respectively. Those of hypercapnic hypoxic carotid bodies were 1.2 (short axis) and 1.5 (long axis) times larger than controls, respectively. The rate of enlargement in hypercapnic hypoxic carotid bodies was lower than in hypocapnic and isocapnic hypoxic carotid bodies. The rate of vascular enlargement in hypercapnic hypoxic carotid bodies was also smaller than in hypocapnic and isocapnic hypoxic carotid bodies. Thus, the enlargement of hypoxic carotid bodies is mainly due to vascular dilation. Different levels of arterial CO2 tension change the peptidergic innervation during chronically hypoxic exposure. The characteristic vascular arrangement was under the control of altered peptidergic innervation. During the course of hypoxic adaptation, the enlargement of the carotid bodies with vascular expansion began soon after the start of hypoxic exposure. During the course of recovery, the shrinking of the carotid bodies with vascular contraction also started at a relatively early period after the termination of chronic hypoxia. These processes during the course of hypoxic adaptation and during the course of recovery were under the control of peptidergic innervation. These findings may provide a standard for further studies of hypoxic carotid bodies.

The distribution and abundance of neuropeptide-containing nerve fibers were examined in the carotid bodies of rats exposed to hypocapnic hypoxia (10% O2 in N2) for 2, 4, and 8 weeks. The carotid bodies after 2, 4, and 8 weeks of hypoxic exposure were enlarged by 1.2-1.5 times in the short axis, and 1.3-1.7 times in the long axis in comparison with the normoxic control ones. The enlarged carotid bodies contained a number of expanded blood vessels. Mean density per unit area (104 µm2) of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive fibers was transiently high in the carotid bodies after 4 weeks of hypoxic exposure, and decreased significantly to nearly or under 50% after 8 weeks of hypoxic exposure. Density of vasoactive intestinal polypeptide (VIP) immunoreactive fibers increased significantly in all periods of hypoxic exposure observed, and was especially high in the carotid bodies after 4 weeks of hypoxic exposure. Density of neuropeptide Y immunoreactive fibers was unchanged in the carotid bodies during hypoxic exposure. These characteristic changes in the density of SP, CGRP, and VIP fibers in the carotid bodies after 4 weeks of hypoxic exposure suggest that the role of these neuropeptide-containing fibers may be different in the carotid bodies after each of three periods of hypoxic exposure, and that the peptidergic innervation after 8 weeks of hypoxic exposure may show an acclimatizing state.

Physical Review Letters

The distribution of substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers in the taste buds of the epiglottis and aryepiglottic folds was compared between normoxic control and chronically isocapnic hypoxic rats (10% O2 and 3-4% CO2 for 3 months). In the normoxic laryngeal taste buds, SP- and CGRP-imrnunoreactive fibers were detected within the taste buds, where they appeared as thin processes with many varicosities. Most CGRP fibers showed coexistence with SP, but a few fibers showed the immunoreactivity of CGRP only. The density of intraand subgemmal SP and CGRP fibers penetrating into the laryngeal taste buds was significantly higher in chronically hypoxic rats than in normoxic control rats. Water intake in the hypoxic rats was significantly lower than in the normoxic rats. These results indicate that the increased density of SP- and CGRP-containing nerve fibers within the laryngeal taste buds is a predominant feature of hypoxic adaptation. The altered peptidergic innervation and reduced water intake support the hypothesis that the laryngeal taste buds are involved in water reception, and that the water reception may be under the control of peptidergic innervation.

The distribution and abundance of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive nerve fibers in four different regions of the laryngeal mucosa were compared between normoxic and chronically hypoxic rats (10% O2 and 3.0-4.0% CO, for 3 months). In the chronically hypoxic laryngeal mucosa, the number of SP and CGRP fibers within and just beneath the epithelium, and around the laryngeal gland was increased in comparison with those in the normoxic controls. Especially in the epiglottic and arytenoid regions, the number of intraepithelial SP fibers was increased remarkably. Most intraepithelial SP and CGRP fibers penetrated into the epithelium to extend to the lumina1 surface. There was no distinct difference in the distribution and abundance of these peptidergic fibers in the mucosa of the normoxic and chronically hypoxic vocal cord regions. These results suggest that the increased density of SP and CGRP fibers within the epithelium of the upper laryngeal mucosa is a predominant feature of hypoxic adaptation, and this may be involved in airway protection, swallowing, and other functions in the chronically hypoxic environment. In addition, the increased SP and CGRP fibers around the laryngeal gland suggest an enhanced mucous secretion, and this may participate in the airway defense mechanism in low O2 conditions.

Distribution of vasoactive intestinal polypeptide (VIP)-immunoreactive nerve fibers and VIPreceptor (VIP-R)-immunoreactive sites in the human submandibular gland were examined by the peroxidaseantiperoxidase method using the specimens taken from patients that had not received radiotherapy. VIP-immunoreactive fibers were found around both serous and mucous acini, the duct system, and those around the mucous acini were more numerous than those around the serous acini. VIP-R immunoreactivity was restricted to the mucous acini and the intercalated duct segment. The serous acini, striated duct, and excretory ducts lacked VIP-R immunoreactivity. These findings suggest that the mucous acinar cells contain VIP-R, and that VIP-R-mediated VIP action is involved in regulating synthesis of viscous saliva and its release.

The amphibian carotid labyrinth, which corresponds to the mammalian carotid body and carotid sinus, is innervated by nerve fibers containing substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY). FMRFamide (FMRF). and somatostatin (SOM). SP, CGRP, VIP, and NPY immunoreactive varicose fibers are more densely distributed in the peripheral portion of the carotid labyrinth than FMRF and SOM fibers. The time of appearance of SP, CGRP. and VIP is different for each. First CGRP fibers, then SP fibers appear at an early stage of larva1 development, and finally VIP fibres are detected at a later stage of larva1 development. Most SP fibres show coexistence with CGRP, and some SP fibres which show coexistence with NPY immunoreactivity are assumed to be continuous with those demonstrating VIP immunoreactivity. This indicates the possibility of coexistence of four different peptides in the same nerve fibers within the labyrinth. In various vasculatures of mammals, it has been shown that SP, CGRP, VIP, and NPY have a vasoactive nature in relation to the vascular smooth muscle cells. On this basis, it seems that the target of the peptidergic innervation in the amphibian carotid labyrinth is the smooth muscle cells which are abundantly distributed in the intervascular stroma. Accordingly, the peptidergic innervation may be involved in the vascular regulatory function of the labyrinth, although the possibility that these peptides participate in the chemoreception cannot be ruled out. In addition, the vascular regulatory function of the labyrinth may be modulated by the interaction of multiple neuropeptides.