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Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein, we propose that CB overstimulation is involved in the etiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes, and obstructive sleep apnoea. We demonstrate that CB activity is increased in IR animal models and that CSN resection prevents CB overactivation and diet-induced IR and HT. Moreover, we show that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases.

SummaryMany nervous system pathologies are associated with increased levels of apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila , Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protective potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD overexpression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids.

The ionic currents of carotid body type I cells and their possible involvement in the detection of oxygen tension (Po2) in arterial blood are unknown. The electrical properties of these cells were studied with the whole-cell patch clamp technique, and the hypothesis that ionic conductances can be altered by changes in PO2 was tested. The results show that type I cells have voltage-dependent sodium, calcium, and potassium channels. Sodium and calcium currents were unaffected by a decrease in PO2 from 150 to 10 millimeters of mercury, whereas, with the same experimental protocol, potassium currents were reversibly reduced by 25 to 50 percent. The effect of hypoxia was independent of internal adenosine triphosphate and calcium. Thus, ionic conductances, and particularly the O2-sensitive potassium current, play a key role in the transduction mechanism of arterial chemoreceptors.

Conde SV, Monteiro EC, Rigual R, Obeso A, Gonzalez C. Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity. J Appl Physiol 112: 2002-2010, 2012. First published April 12, 2012 doi:10.1152/japplphysiol.01617.2011.-Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O 2) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O 2) and in response to hypoxias of different intensities (10, 5, and 2% O 2) to study the release pathways. We found that ZM241385, an A 2 antagonist, decreased the CSN discharges evoked by 0 and 7% O 2 by 30.8 and 72.5%, respectively. Suramin, a P 2X antagonist, decreased the CSN discharges evoked by 0 and 7% O 2 by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O 2 levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia.adenosine; hypoxia; carotid body CAROTID BODIES (CB) are major peripheral chemoreceptor organs that release neurotransmitters in response to hypoxia, generating action potentials at the carotid sinus nerve (CSN) that are integrated in the brain stem to induce a hyperventilatory compensatory response (17). Among the neurotransmitters released in the CB are adenosine and ATP (1-3). One of the first studies on the effects of ATP on CSN activity was carried out by McQueen and Ribeiro (24) where they showed in vivo in the cat CB that ATP increased CSN activity in a dosedependent manner. Additional experiments led them to conclude that the excitatory action of ATP was due to the adenosine formed by its extracellular degradation. More recently, Zhang and co-workers (47) showed that the coapplication of blockers of nicotinic and P2X receptors, hexamethonium and suramin, respectively, in cocultures of glomus cells and "juxtaposed" petrosal ganglions completely abolished the hypoxiaevoked excitatory postsynaptic responses. They concluded that ATP and ACh, acting as cotransmitters, supported the s...

We tested the hypothesis that long-term caffeine intake prevents the development of insulin resistance and hypertension in two pathological animal models: the high-fat (HF) and the high-sucrose (HSu) diet rat. We used six groups of animals: control; caffeine-treated (Caff; 1 g/l in drinking water during 15 d); HF; caffeine-treated HF (HFCaff); HSu; caffeine-treated HSu (HSuCaff). Insulin sensitivity was assessed using the insulin tolerance test. Blood pressure, weight gain, visceral fat, hepatic glutathione, plasma caffeine, insulin and NO, and serum NEFA and catecholamines were measured. Caffeine reversed insulin resistance and hypertension induced by both the HF and HSu diets. In the HF-fed animals caffeine treatment restored fasting insulin levels to control values and reversed increased weight gain and visceral fat mass. In the HSu group, caffeine reversed fasting hyperglycaemia and restored NEFA to control values. There were no changes either in plasma NO or in hepatic glutathione levels. In contrast, caffeine totally prevented the increase in serum catecholamines induced by HF and HSu diets. To test the hypothesis that inhibition of the sympathetic nervous system prevents the development of diet-induced insulin resistance we administered carvedilol, an antagonist of b1, b2 and also a1 adrenoceptors, to HF and HSu rats. Carvedilol treatment fully prevented diet-induced insulin resistance and hypertension, mimicking the effect of caffeine. We concluded that long-term caffeine intake prevented the development of insulin resistance and hypertension in HF and HSu models and that this effect was related to a decrease in circulating catecholamines.

AimsThe mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV.Methods and resultsCeramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of KV currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response.ConclusionnSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV.

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