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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central nervous system plays an important role in the regulation of blood pressure via the sympathetic nervous system. Abnormal regulation of the sympathetic nerve activity is involved in the pathophysiology of hypertension. In particular, the brain stem, including the nucleus tractus solitarii (NTS) and the rostral ventrolateral medulla (RVLM), is a key site that controls and maintains blood pressure via the sympathetic nervous system. Nitric oxide (NO) is a unique molecule that influences sympathetic nerve activity. Rho-kinase is a downstream effector of the small GTPase, Rho, and is implicated in various cellular functions. We developed a technique to transfer adenovirus vectors encoding endothelial nitric oxide synthase and dominant-negative Rho-kinase into the NTS or the RVLM of rats in vivo. We applied this technique to hypertensive rats to explore the physiological significance of NO and Rho-kinase.
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PMID:Adenovirus-mediated gene transfer into the brain stem to examine cardiovascular function: role of nitric oxide and Rho-kinase. 1476 38

Hypertension is a cardiovascular disorder characterized by increased peripheral vascular resistance and/or vascular structural remodeling. Recently, rapidly growing evidence from hypertensive animal models suggests that small GTPase Rho and its downstream effector, Rho-kinase, play an important role in the pathogenesis of hypertension. Activation of the Rho/Rho-kinase pathway is essential for smooth muscle contractility in hypertension. A greater RhoA expression and an enhanced RhoA activity have been observed in aortas of hypertensive rats, such as genetic spontaneously hypertensive rats and N(omega)-nitro-L-arginine methyl ester-induced hypertension. The enhanced RhoA expression and activity was already observed in young spontaneously hypertensive rats before the onset of hypertension. These results suggest that both genetic factors and blood pressure can upregulate RhoA expression. Moreover, Y-27632 or fasudil, the specific Rho-kinase inhibitors, markedly decreased blood pressure in various hypertensive model rats, but did not in normotensive animals. In addition, Rho-kinase inhibitors have been shown to inhibit hypertensive vascular lesion formation. Therefore, Rho-kinase inhibitors may have a therapeutic potential for the treatment of hypertensive patients.
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PMID:Rho-kinase, a potential therapeutic target for the treatment of hypertension. 1560 12

Rho-kinase is a signaling molecule that occurs downstream of the small GTPase Rho, which mediates various cellular functions. The Rho/Rho-kinase pathway plays an important role in pathophysiology and progression of various cardiovascular diseases such as hypertension, coronary vasospasm, angina pectoris, and restenosis after percutaneous coronary intervention, all of which are related to arteriosclerosis/atherosclerosis changes of the vasculature. Activation of the Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes of the blood vessels and affects cardiac myocytes. Evidence from in vitro and in vivo studies suggests that Rho-kinase inhibitors have beneficial effects on cardiovascular diseases, particularly arteriosclerosis and coronary vasospasm. Furthermore, activation of the Rho/Rho-kinase pathway contributes to blood pressure regulation via the central sympathetic nervous system. There is evidence to suggest that Rho-kinase is involved in angiotensin II-induced cardiac hypertrophy and endothelial dysfunction, and preliminary data indicate that inhibition of Rho-kinase may be beneficial in vascular disorders such as pulmonary arterial hypertension and erectile dysfunction. Fasudil is currently the only Rho-kinase inhibitor available for clinical use and it is approved in Japan for the prevention of vasospasm in patients with subarachnoid hemorrhage. Emerging clinical data have shown that oral fasudil 80 mg three times daily is effective in preventing myocardial ischemia in patients with stable angina pectoris. Rho-kinase represents a new target for the management of cardiovascular diseases and further studies are needed to define the therapeutic potential of Rho-kinase inhibitors.
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PMID:Therapeutic potential of rho-kinase inhibitors in cardiovascular diseases. 1563 36

The small GTPase Rho and its downstream effector Rho-kinase contribute to agonist-induced vascular contraction via Ca2+ sensitization. Reasonably selective pharmacological inhibitors of these proteins have been developed and are now widely used experimentally to investigate the role of this signaling pathway in vascular function. Rho and Rho-kinase have attracted increasing clinical interest as a result of emerging evidence for their roles in the pathogenesis of several cardiovascular disorders, including hypertension, coronary and cerebral vasospasm, atherosclerosis and diabetes, and are now considered important future therapeutic targets. A major challenge lies in further developing selective inhibitors of this pathway beyond experimental use. Consideration should perhaps also be given to widening the application of existing clinical drugs now known to also interfere with Rho-Rho-kinase signaling.
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PMID:Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. 1637 97

Erectile dysfunction (ED) is a highly prevalent and often under-treated condition. Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between contractile and relaxant factors, which control the degree of contraction of penile corporal cavernosal smooth muscles and, thus, determine the erectile state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of ED. Recent studies have revealed important roles for the small GTPase RhoA and its effector, Rho-kinase in regulating cavernosal smooth muscle tone. The RhoA/Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca(2+)-sensitization in smooth muscle contraction. Changes in this pathway may contribute to ED in various patient subgroups (e.g. hypertension, diabetes, hypogonadism). This review summarizes the importance of Rho-kinase signaling in the erectile response and introduces the evidence pointing to RGS-containing Rho-guanine nucleotide exchange factors (GEFs) as critical mediators of RhoA-GTPase activation in cavernosal smooth muscle and its possible compartmentalization in the caveolae. In addition, we suggest that the design of selective inhibitors of these GEFs might represent a novel class of pharmacological agents to treat ED.
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PMID:Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction. 1637 8

Recent studies have indicated the importance of cholesterol-rich membrane lipid rafts (LRs) in oxidative stress-induced signal transduction. Reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases, the major sources of reactive oxygen species, are implicated in cardiovascular diseases, including hypertension. We tested the hypothesis that NADPH oxidase subunits and activity are regulated by LRs in human renal proximal tubule cells. We report that a high proportion of p22(phox) and the small GTPase Rac1 are expressed in LRs in human renal proximal tubule cells. The D(1)-like receptor agonist, fenoldopam (1 micromol/L per 20 minutes) dispersed Nox subunits within LRs and non-LRs and decreased oxidase activity (30.7+/-3.3%). In contrast, cholesterol depletion (2% methyl-beta-cyclodextrin [beta CD]) translocated NADPH oxidase subunits out of LRs and increased oxidase activity (154.0+/-10.5% versus control, 103.1+/-3.4%), which was reversed by cholesterol repletion (118.9+/-9.9%). Moreover, NADPH oxidase activation by beta CD (145.5+/-9.0%; control: 98.6+/-1.6%) was also abrogated by the NADPH oxidase inhibitors apocynin (100.4+/-3.2%) and diphenylene iodonium (9.5+/-3.3%). Furthermore, beta CD-induced reactive oxygen species production was reversed by knocking down either Nox2 (81.0+/-5.1% versus beta CD: 162.0+/-2.0%) or Nox4 (108.0+/-10.8% versus beta CD: 152.0+/-9.8%). We have demonstrated for the first time that disruption of LRs results in NADPH oxidase activation that is abolished by antioxidants and silencing of Nox2 or Nox4. Therefore, in human renal proximal tubule cells, LRs maintain NADPH oxidase in an inactive state.
Hypertension 2008 Feb
PMID:Lipid rafts keep NADPH oxidase in the inactive state in human renal proximal tubule cells. 1819 59

G protein-coupled receptors (GPCRs) are important targets for medicinal agents. Four different G protein families, G(s), G(i), G(q), and G(12), engage in their linkage to activation of receptor-specific signal transduction pathways. G(12) proteins were more recently studied, and upon activation by GPCRs they mediate activation of RhoGTPase guanine nucleotide exchange factors (RhoGEFs), which in turn activate the small GTPase RhoA. RhoA is involved in many cellular and physiological aspects, and a dysfunction of the G(12/13)-Rho pathway can lead to hypertension, cardiovascular diseases, stroke, impaired wound healing and immune cell functions, cancer progression and metastasis, or asthma. In this study, regulator of G protein signaling (RGS) domain-containing RhoGEFs were tagged with enhanced green fluorescent protein (EGFP) to detect their subcellular localization and translocation upon receptor activation. Constitutively active Galpha(12) and Galpha(13) mutants induced redistribution of these RhoGEFs from the cytosol to the plasma membrane. Furthermore, a pronounced and rapid translocation of p115-RhoGEF from the cytosol to the plasma membrane was observed upon activation of several G(12/13)-coupled GPCRs in a cell type-independent fashion. Plasma membrane translocation of p115-RhoGEF stimulated by a GPCR agonist could be completely and rapidly reversed by subsequent application of an antagonist for the respective GPCR, that is, p115-RhoGEF relocated back to the cytosol. The translocation of RhoGEF by G(12/13)-linked GPCRs can be quantified and therefore used for pharmacological studies of the pathway, and to discover active compounds in a G(12/13)-related disease context.
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PMID:Reversible translocation of p115-RhoGEF by G(12/13)-coupled receptors. 1832 May 79

Reactive oxygen species (ROS) including superoxide (O(2)(.-)) and hydrogen peroxide (H(2)O(2)) are produced endogenously in response to cytokines, growth factors; G-protein coupled receptors, and shear stress in endothelial cells (ECs). ROS function as signaling molecules to mediate various biological responses such as gene expression, cell proliferation, migration, angiogenesis, apoptosis, and senescence in ECs. Signal transduction activated by ROS, "oxidant signaling," has received intense investigation. Excess amount of ROS contribute to various pathophysiologies, including endothelial dysfunction, atherosclerosis, hypertension, diabetes, and acute respiratory distress syndrome (ARDS). The major source of ROS in EC is a NADPH oxidase. The prototype phagaocytic NADPH oxidase is composed of membrane-bound gp91phox and p22hox, as well as cytosolic subunits such as p47(phox), p67(phox) and small GTPase Rac. In ECs, in addition to all the components of phagocytic NADPH oxidases, homologues of gp91(phox) (Nox2) including Nox1, Nox4, and Nox5 are expressed. The aim of this review is to provide an overview of the emerging area of ROS derived from NADPH oxidase and oxidant signaling in ECs linked to physiological and pathophysiological functions. Understanding these mechanisms may provide insight into the NADPH oxidase and oxidant signaling components as potential therapeutic targets.
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PMID:NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. 1878 13

Reactive oxygen species (ROS) are essential for efficient and proper execution of a large number of cellular processes including signalling induced by exogenous factors. However, ROS are highly reactive in nature and excessive or prolonged ROS formation can result in considerable damage to cellular constituents and is implicated in the onset of a large variety of diseases as well as in the process of ageing [reviewed in [1] T.M. Paravicini, R.M. Touyz, Redox signaling in hypertension, Cardiovasc. Res. 71 (2006) 247-258, [2] P. Chiarugi, From anchorage dependent proliferation to survival: lessons from redox signalling, IUBMB life 60 (2008) 301-307, [3] M. Valko, D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, J. Telser, Free radicals and antioxidants in normal physiological functions and human disease, Int. J. Biochem. Cell Biol. 39 (2007) 44-84]. Management of ROS to prevent potential damage, yet enabling its signalling function is achieved through numerous enzyme systems e.g. peroxidases, superoxide dismutases etc. and small molecules e.g. glutathione that collectively form the cellular anti-oxidant system. The O-class of Forkhead box (FOXO) transcription factors regulates amongst others cellular resistance against oxidative stress [[4] Y. Honda, S. Honda, The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans, Faseb J. 13 (1999) 1385-1393]. In turn FOXOs themselves are regulated by ROS and cellular oxidative stress results in the activation of FOXOs [[5] M.A. Essers, S. Weijzen, A.M. de Vries-Smits, I. Saarloos, N.D. de Ruiter, J.L. Bos, B.M. Burgering, FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK, EMBO J. 23 (2004) 4802-4812]. A prominent feature of ROS-induced FOXO activation is ROS-induced binding of beta-catenin to FOXO [[6] M.A. Essers, L.M. de Vries-Smits, N. Barker, P.E. Polderman, B.M. Burgering, H.C. Korswagen, Functional interaction between beta-catenin and FOXO in oxidative stress signaling, Science (New York, NY) 308 (2005) 1181-1184, [7] M. Almeida, L. Han, M. Martin-Millan, C.A. O'Brien, S.C. Manolagas, Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription, J. Biol. Chem. 282 (2007) 27298-27305, [8] D. Hoogeboom, M.A. Essers, P.E. Polderman, E. Voets, L.M. Smits, B.M. Burgering, Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity, J. Biol. Chem. 283 (2008) 9224-9230]. However, ROS affect many transcriptional programs besides that of FOXOs. Here, we discuss the recent progress in our understanding as to how ROS may regulate the interplay between some of the ROS-sensitive transcription factors through diverting beta-catenin binding to these transcription factors. We propose that beta-catenin acts as a key switch between the various ROS-sensitive transcription programs.
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PMID:Should I stay or should I go: beta-catenin decides under stress. 1926 9

Strong evidence supports the ability of the aldosterone/mineralocorticoid receptor (MR) system to dominate long-term blood pressure control. It is also increasingly recognized as an important mediator of cardiovascular and renal diseases, particularly in the presence of excessive salt intake. In a subgroup of individuals with metabolic syndrome, adipocyte-derived aldosterone-releasing factors cause inappropriate secretion of aldosterone in the adrenal glands during salt loading, resulting in the development of salt-induced hypertension and cardiac and renal damage. On the other hand, emerging data reveal that aldosterone is not a sole regulator of MR activity. We have identified the signaling crosstalk between MR and small GTPase Rac1 as a novel pathway to facilitate MR signaling. Such a local control system for MR can also be relevant to the pathogenesis of salt-sensitive hypertension, and future studies will clarify the detailed mechanism for the intricate regulation of the aldosterone/MR cascade.
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PMID:The kidneys and aldosterone/mineralocorticoid receptor system in salt-sensitive hypertension. 2120 53


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