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.

Absence of bioactivity of lipid derivatives of serotonin.

BACKGROUND: Serotonin (5-HT) and its receptors are present in central, the brain stem, and peripheral, the carotid body, tissues controlling the ventilatory responses to hypoxia. The exact action of serotonin and its nature are, however, unsettled. We hypothesized that the discrepant results on the ventilatory action of serotonin could be caused by the inability of serotonin to penetrate into the brain or the plasma membrane lipid bilayers, the target site of signal transduction cascades, after its exogenous administration. OBJECTIVE: To study the penetrability of novel lipid derivatives of serotonin of varying fatty acid chain length and number of saturated/unsaturated bonds, the oleic, caprylic, and caprolic amides of 5-HT, into the brain, and their functional effects on the hypoxic ventilatory response in awake rats after systemic administration. MATERIAL AND METHODS: Adult Wistar rats were used for the experiments. In the biochemical part of the study, the presence and stability of the compounds tested, after i.p. injection, was assessed in brain extracts using spectrophotometry and thin-layered chromatography. In the functional part, the ventilatory responses to 8 and 12% hypoxia were compared before and 1 h after the compound administration using a whole body plethysmography. RESULTS: The "lipidized" serotonin compounds turned out to be stable in brain extracts in vitro for up to 3 h of the test. However, we could not substantiate the presence of any of the compounds in the brain, with either method used, after i.p. administration. Likewise, none of the compounds had any appreciable effect on the profile of the stimulatory hypoxic ventilatory response. CONCLUSIONS: Synthetically attaching lipophilic groups to the serotonin molecule does not make it penetrate into the brain. The lack of serotonin penetrability likely depends on the planarity of its molecule, as it does not seem to depend on the size, number of carbons or bond saturation of the "lipidized" molecules. Such molecules do not directly interfere with the carotid chemoreceptor-mediated hypoxic ventilatory response. The study failed to substantiate the bioactive potential of the lipid derivatives of serotonin.