Obesity is a widespread health concern that is associated with an increased prevalence of hypertension and cardiovascular disease. Both obesity and hypertension have independently been associated with increased levels of inflammatory cytokines and immune cells within specific brain regions, as well as increased activity of the renin-angiotensin system (RAS). To test the hypothesis that high-fat diet (HFD) induced obesity leads to an angiotensin-II (Ang-II)-dependent increase in inflammatory cells within specific forebrain regions that are important for cardiovascular regulation, we first assessed microglial activation, astrocyte activation, inflammation and RAS component gene expression within selected metabolic and cardiovascular control centers of the forebrain in adult male C57BL/6 mice given either a HFD or a low-fat diet (LFD) for 8 weeks. Subsequently, we assessed the necessity of the paraventricular nucleus of the hypothalamus (PVN) angiotensin type-1a (AT1a) receptor for these responses by using the Cre/lox system in mice to selectively delete the AT1a receptor from the PVN. These studies reveal that in addition to the arcuate nucleus of the hypothalamus (ARC), the PVN and the subfornical organ (SFO), two brain regions that are known to regulate blood pressure and energy balance, also initiate proinflammatory responses after the consumption of a diet high in fat. They further indicate that some, but not all, of these responses are reversed upon deletion of AT1a specifically within the PVN.
Intravenous immunoglobulins (IVIg) have been used successfully as an immunomodulating treatment for patients with inflammatory diseases of the central nervous system (CNS) including multiple sclerosis (MS). It was shown previously that IVIg could modulate the functions of microglia, the main immune cell in the CNS. We have compared five commercially available IVIg preparations on their capacity to modulate tumor necrosis factor (TNF)-alpha secretion and nitric oxide production in cultured microglia. All preparations induced a dose-dependent stimulation of TNF-alpha secretion as measured by ELISA. There were some small differences between preparations consisting of IgG, while the preparation enriched for IgM and IgA induced a considerably higher TNF-alpha production at 1 mg/mL and 10 mg/mL. Similar results were seen for nitric oxide production as measured indirectly by the Griess reaction. These results indicate that IgM/IgA-enriched IVIg may be a more potent immunomodulator than pure IgG preparations on inflammatory reactions in the CNS.
. Muscarinic receptor activation affects pulmonary artery contractility in sheep: the impact of maturation and chronic hypoxia on endothelium-dependent and endothelium-independent function. High Alt Med Biol. 17:122-132, 2015.-Muscarinic receptor activation in the pulmonary vasculature can cause endothelium-dependent vasodilation and smooth muscle-dependent vasoconstriction. Chronic hypoxia (CH) can modify both of these responses. This study aimed to assess the combined influence of CH and maturation on endothelium-dependent and endothelium-independent muscarinic-induced vasoreactivity. This was accomplished by performing wire myography on endothelium-intact or endothelium-disrupted pulmonary arterial rings isolated from normoxic or CH fetal and adult sheep. In endothelium-intact arteries, vasodilation was evaluated using cumulative bradykinin doses in phenylephrine and carbachol precontracted pulmonary arterial segments; and vasoconstriction was examined using cumulative doses of carbachol following bradykinin predilation. Effects of nonselective (atropine) and selective M1 (pirenzepine), M2 (AFDX116), and M3 (4-DAMP and Dau5884) muscarinic receptor antagonists were assessed in disrupted arteries. In normoxic arteries, bradykinin relaxation was twofold greater in the adult compared to fetus, while carbachol contraction was fourfold greater. In adult arteries, CH increased bradykinin relaxation and carbachol contraction. In vessels with intact endothelium, maturation and CH augmented maximal response and efficacy for carbachol constriction and bradykinin relaxation. Approximately 50%-80% of adult normoxic and CH endothelium-disrupted arteries contracted to acetylcholine, while *50% of fetal normoxic and *10% of CH arteries responded. Atropine reduced carbachol-induced contraction in all vessels. Adult normoxic vessels were most responsive to M3 antagonism, fetal to M2 antagonism, while M1 inhibition had no effect. Overall, muscarinic-induced pulmonary arterial contraction is partially endothelium dependent and appears to develop after birth. Fetuses are more reliant on M3 receptors while M2 receptors predominate in adults, whereas CH augments muscarinic-dependent pulmonary vasoconstriction in both.
Serotonin (5‐HT) signaling plays important roles in pulmonary vascular contractility and development. Several studies illustrate that 5‐HT mediated pulmonary arterial (PA) contractility adapts with development in sheep and rat and in response to chronic hypoxic (CH) stress in the rat. Our studies show that 5‐HT induced Ca2+ elevations in fewer PA myocytes from fetal relative to adult sheep suggesting there may be increases in receptor expression associated with maturation. Using wire myography approaches, the present study tested the hypothesis that CH and maturation increase the potency as well as efficacy of 5‐HT‐mediated PA contractility in sheep. The results show the EC50 to 5‐HT was unchanged with maturation in PA from normoxic sheep. However, the potency to 5‐HT was reduced with CH in fetus and increased in adult. The tension developed by 10 μM 5‐HT increased with maturation but not CH and no differences were observed when normalized to the tension due to 125 mM KCl. Moreover, in all groups the contractility to 1 μM 5‐HT was completely abolished by 100 nM Ketanserin, a selective 5‐HT2A antagonist. In conclusion, based on this and our previous studies the changes in 5‐HT efficacy and potency with maturation and CH are most likely due to altered receptor number, second messenger coupling or phenotypic alterations in PA myocyte function. (Support from NIH, Sigma Xi, and UM)
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