Hypoxic Ventilatory Reactivity in Experimental Diabetes.

Diabetes, apart from generalized neuropathy and microangiopathy, involves tissue hypoxia, which may drive chronic proinflammatory state. However, studies on the ventilatory control in diabetes are sparse and conflicting. In this study we examined the function and morphology of diabetic carotid bodies (CBs). Diabetes was evoked in Wistar rats with streptozotocin (70 mg/kg, i.p.). The acute hypoxic ventilatory responses (HVR) to 12 and 8 % O(2) were investigated in conscious untreated rats after 2 and 4 weeks in a plethysmographic chamber. CBs were dissected and subjected to morphologic investigations: (1) electron transmission microscopy for ultrastructure and (2) laser scanning confocal microscopy to visualize the microvascular bed in sections labeled with the lectin Griffonia simplicifolia-I (GSI), an endothelial cell marker, and fluorescein isothiocyanate (FITC). All findings were referenced to the normal healthy rats. We found that diabetes distinctly dampened the HVR. At the ultrastructural level, the diabetic CB displayed proliferation of connective tissue and neovascularization deranging the interglomal structure, and lengthening the O(2) diffusion path from capillaries to chemoreceptor cells. The chemoreceptor cells remained largely unchanged. The endothelial cell labeling confirmed the intensive angiopathy and the induction of microvessel growth. We conclude that diabetes hampers the chemical regulation of ventilation due to remodeling of CB parenchyma, which may facilitate chronic hypoxia and inflammation in the organ.

Ultrastructural degradation of the carotid body in the aged rat: is there a role for atherosclerosis in the main carotid arteries?

In this study we examined the potential role of atherosclerosis in the main arteries supplying blood to the carotid body in the organ's morphological degradation with age. We addressed this issue by comparing the ultrastructural picture of carotid bodies and of fragments of the carotid artery bifurcation in two age-extreme groups of rats: young - 3 months old and senescent - 24 months old. Tissues were excised under surgical anesthesia, fixed in aldehydes, and processed for transmission electron microscopy. We found that the old carotid body parenchyma exhibited profound degenerative changes. Chemoreceptor cells were at various stages of atrophy, ranging from swollen mitochondria and fewer secretory vesicles to dark dehydrated cells. In contrast, the senescent carotid artery bifurcation was little different from that in young rats. Particularly, endothelial cells were in perfect condition. There were some changes in deeper arterial wall layers such as breaks in the continuity of elastic bands or a subtly different phenotype of smooth muscle cells. No foam cells or calcium build-ups were found in the arterial walls. Such changes correspond to the process of arterial wall stiffening in old age rather than to the outright atherosclerosis. Lack of atherosclerosis in the common carotid arteries, which could hamper blood flow, argues against its playing a role in the morphological age-changes in the carotid bodies.

The aging carotid body.

The respiratory system is subject to the aging process, which could limit its responsiveness to hyperventilatory stimuli. Attenuation of the ventilatory response to hypoxia in old age is, as yet, an unresolved issue. Such attenuation may be germane for the pathogenesis of respiratory disorders developing more often in elderly subjects. The aim of this study was to determine the potential adverse effects of age on the morphology and function of carotid bodies. Morphology was studied at the level of electron microscopy on carotid bodies dissected from adult young (3 months) and old (>2 years) rats and function by comparing the hypoxic ventilatory response in populations of young (mean age 24 years) and old (mean age 71 years) female subjects. The human protocol consisted of a progressive hypoxia test, based on a rebreathing technique in a closed system. The hypoxic ventilatory response was evaluated from the slopes of minute ventilation on arterial oxygen saturation. The results of the morphological study showed degenerative changes developing with age in the ultrastructure of carotid bodies. On the other side, respiratory responses to hypoxia in old women were well preserved and were no less than those in young women. Therefore, a discrepancy appeared between the morphological and functional aspects. These findings suggest development of compensatory mechanisms in brain respiratory areas which maintain primary defensive reflexes, such as the hyperventilation of hypoxia.

NMDA glutamate receptor antagonism and the ventilatory response to hypoxia in the anesthetized rat.

This study seeks to discern the influence of the NMDA glutamate-mediated pathway in the early stimulatory and late depressant phases of the hypoxic ventilatory response. We addressed this issue by recording ventilation before and after intravenous administration of the NMDA receptor antagonist MK-801 during acute, steady-state hypoxic challenges in the anesthetized, spontaneously breathing rats. Minute ventilation and its volume and frequency components were calculated and compared at the peak and nadir of the hypoxic response. We found that NMDA receptor antagonism appreciably affected both ventilatory phases of hypoxia. The early stimulation of ventilation was attenuated and the late depression was accentuated. The latter consisted of abolishment of the characteristic sustenance of hypoxic ventilation above the baseline level in the depressant phase, so that ventilation declined down to the baseline after NMDA receptor blockade. The inability to uphold ventilation in the depressant phase suggests that the NMDA glutamate-mediated pathway is operative in shaping the late hypoxic ventilatory response. The role of the glutamatergic pathway may thus be extended beyond the hitherto recognized early ventilatory stimulation of hypoxia.