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Zhou Y.-B.,Nanjing Medical University | Sun H.-J.,Nanjing Medical University | Chen D.,Nanjing Medical University | Liu T.-Y.,Nanjing Medical University | And 5 more authors.
Hypertension | Year: 2014

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide family, which shares the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs). This study investigated the effects of IMD in paraventricular nucleus (PVN) on renal sympathetic nerve activity and mean arterial pressure and its downstream mechanism in hypertension. Rats were subjected to 2-kidney 1-clip (2K1C) surgery to induce renovascular hypertension or sham operation. Acute experiments were performed 4 weeks later under anesthesia. IMD mRNA and protein were downregulated in 2K1C rats. Bilateral PVN microinjection of IMD caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in 2K1C rats than in sham-operated rats, which were prevented by pretreatment with adrenomedullin receptor antagonist AM22-52 or nonselective nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester, and attenuated by selective neuronal NO synthase inhibitor N-propyl-l-arginine hydrochloride or endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-l-ornithine dihydrochloride. AM22-52 increased renal sympathetic nerve activity and mean arterial pressure in 2K1C rats but not in sham-operated rats, whereas calcitonin/calcitonin gene-related peptide receptor antagonist calcitonin/calcitonin gene-related peptide 8-37 had no significant effect. CRLR and RAMP3 mRNA, as well as CRLR, RAMP2, and RAMP3 protein expressions, in the PVN were increased in 2K1C rats. Microinjection of IMD into the PVN increased the NO metabolites (NOx) level in the PVN in 2K1C rats, which was prevented by AM22-52. Chronic PVN infusion of IMD reduced, but AM22-52 increased, blood pressure in conscious 2K1C rats. These results indicate that IMD in the PVN inhibits sympathetic activity and attenuates hypertension in 2K1C rats, which are mediated by adrenomedullin receptors (CRLR/RAMP2 or CRLR/RAMP3) and its downstream NO. © 2013 American Heart Association, Inc. Source

Qi R.,Peking University | Qi R.,Key Laboratory of Molecular Cardiovascular science | Qi R.,University of Michigan | Mullen D.G.,University of Michigan | And 2 more authors.
Molecular Pharmaceutics | Year: 2010

The GM1/caveolin-1 lipid raft mediated endocytosis mechanism was explored for generation 5 and 7 poly(amidoamine) dendrimer polyplexes employing the Cos-7, 293A, C6, HeLa, KB, and HepG2 cell lines. Expression levels of GM1 and caveolin-1 were measured using dot blot and Western blot, respectively. The level of GM1 in the cell plasma membrane was adjusted by incubation with exogenous GM1 or ganglioside inhibitor PPMP, and the level of CAV-1 was adjusted by upregulation with the adenovirus vector expressed caveolin-1 (AdCav-1). Cholera toxin B subunit was employed as a positive control for uptake in all cases. No evidence was found for a GM1/caveolin-1 lipid raft mediated endocytosis mechanism for the generation 5 and 7 poly(amidoamine) dendrimer polyplexes. © 2010 American Chemical Society. Source

Li W.,Peking University | Tang C.,Peking University | Tang C.,Key Laboratory of Molecular Cardiovascular science | Jin H.,Peking University | Du J.,Peking University
Atherosclerosis | Year: 2011

Objective: This study was designed to examine the effect of sulfur dioxide (SO2) on atherosclerotic progression and endogenous vascular hydrogen sulfide (H2S) in rats with atherosclerosis (AS). Methods: Twenty-eight male rats were randomly divided into control, AS and AS+SO2 groups. Rats were given a single dose of vitamin D3 and fed a high-cholesterol diet for 8 weeks to induce AS. Plasma lipids, aortic ultrastructure, and atherosclerotic lesions were detected at the termination of experiment. Plasma and aortic SO2 were measured using high-performance liquid chromatography, and aspartate aminotransferase (AAT) 1 and AAT2 mRNAs were detected by real-time PCR. Plasma and aortic H2S levels were determined with a sulfide-sensitive electrode. Cystathionine-γ-lyase (CSE) mRNA and protein expression was detected. Plasma glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities, malondialdehyde (MDA) and nitric oxide (NO) contents, inducible NO synthase (iNOS) and eNOS activities, and aortic SOD1 and SOD2 expressions were detected. Results: Marked atherosclerotic lesions with elevated levels of TC and LDL-C were observed in AS rats. While, there were decreased plasma SO2 levels and aortic SO2 production, with a reduced aortic AAT activity in atherosclerotic rats. Plasma GSH-Px and SOD activities were decreased but MDA level increased. Plasma NO content and iNOS activity were also increased. SO2 donor, however, significantly decreased the atherosclerotic lesions with an increased aortic H2S/CSE pathway. It elevated plasma GSH-Px and SOD activities, reduced plasma MDA level, and increased NO/NOS pathway. Conclusions: SO2 has a marked anti-atherogenic effect with an increase in endogenous H2S production in rats with AS. © 2011 Elsevier Ireland Ltd. Source

Bankir L.,French Institute of Health and Medical Research | Yang B.,Peking University | Yang B.,Key Laboratory of Molecular Cardiovascular science
Kidney International | Year: 2012

The mechanism by which urine is concentrated in the mammalian kidney remains incompletely understood. Urea is the dominant urinary osmole in most mammals and may be concentrated a 100-fold above its plasma level in humans and even more in rodents. Several facilitated urea transporters have been cloned. The phenotypes of mice with deletion of the transporters expressed in the kidney have challenged two previously well-accepted paradigms regarding urea and sodium handling in the renal medulla but have provided no alternative explanation for the accumulation of solutes that occurs in the inner medulla. In this review, we present evidence supporting the existence of an active urea secretion in the pars recta of the proximal tubule and explain how it changes our views regarding intrarenal urea handling and UT-A2 function. The transporter responsible for this secretion could be SGLT1, a sodium-glucose cotransporter that also transports urea. Glucagon may have a role in the regulation of this secretion. Further, we describe a possible transfer of osmotic energy from the outer to the inner medulla via an intrarenal Cori cycle converting glucose to lactate and back. Finally, we propose that an active urea transporter, expressed in the urothelium, may continuously reclaim urea that diffuses out of the ureter and bladder. These hypotheses are all based on published findings. They may not all be confirmed later on, but we hope they will stimulate further research in new directions. © 2012 International Society of Nephrology. Source

Gao Y.,Peking University | Gao Y.,Key Laboratory of Molecular Cardiovascular science
Journal of Cardiovascular Pharmacology | Year: 2016

Soluble guanylyl cyclase (sGC) is the principal enzyme in mediating the biological actions of nitric oxide. On activation, sGC converts guanosine triphosphate to guanosine 3′,5′-cyclic monophosphate (cGMP), which mediates diverse physiological processes including vasodilation, platelet aggregation, and myocardial functions predominantly by acting on cGMP-dependent protein kinases. Cyclic GMP has long been considered as the sole second messenger for sGC action. However, emerging evidence suggests that, in addition to cGMP, other nucleoside 3′,5′-cyclic monophosphates (cNMPs) are synthesized by sGC in response to nitric oxide stimulation, and some of these nucleoside 3′,5′-cyclic monophosphates are involved in various physiological activities. For example, inosine 3′,5′-cyclic monophosphate synthesized by sGC may play a critical role in hypoxic augmentation of vasoconstriction. The involvement of cytidine 3′,5′-cyclic monophosphate and uridine 3′,5′-cyclic monophosphate in certain cardiovascular activities is also implicated. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

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