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

The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A(2). Also, an increase in the amount/activity of intracellular Ca(2+) concentration, protein kinase C, Rho kinase, and mitogen-activated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN.
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PMID:Cellular mediators of renal vascular dysfunction in hypertension. 1922 45

Serotonin (5-HT) stimulates pulmonary artery smooth muscle cell proliferation and has been associated with pulmonary arterial hypertension (PAH). Bone morphogenetic protein receptor 2 (BMPR2) mutations similarly have been linked to PAH. However, possible crosstalk between 5-HT and BMPR signaling remains poorly characterized. We report here that 5-HT activates Smads 1/5/8 in bovine and human pulmonary artery smooth muscle cells (SMCs) and causes translocation of these Smads from cytoplasm to the nucleus. DN BMPR1A blocked 5-HT activation of Smads 1/5/8 by 5-HT and BMPR1A overexpression enhanced it. Activation of Smads by 5-HT occurred through the 5-HT 1B/1D receptor as it was blocked with the inhibitor GR 55562 but unaffected by inhibitors of the 5-HT transporter and a variety of 5-HT receptors. Activation of the Smads by 5-HT depended on Rho/Rho kinase signaling as it was blocked by Y27632, but unaffected by inhibitors of PI3K or MAPK. Transfection of cells with BMPR1A and ligation of the BMP receptor with BMP-2 also activated GTP-Rho A of these SMCs, while DN BMPR1A blocked the activation. 5-HT stimulated an increase in serine/threonine phosphorylation of BMPR1A, supporting the activation of BMPR1A by 5-HT in SMCs. Infusion of 5-HT into mice with miniosmotic infusion pumps caused activation of Smads 1/5/8 in lung tissue, demonstrating the effect in vivo. The studies support a unique concept that 5-HT transactivates the serine kinase receptor, BMPR 1A, to activate Smads 1/5/8 via Rho and Rho kinase in pulmonary artery SMCs. Rho and Rho kinase also participate in the activation of Smads by BMP.
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PMID:Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells. 1924 13

Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of < 2.5 microm (PM(2.5)) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM(2.5) or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM(2.5) exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM(2.5) exposure along with increased expression of the guanine exchange factors (GEFs) PDZ-RhoGEF and p115 RhoGEF in PM(2.5)-exposed mice. Parallel with increased RhoA activation, PM(2.5) exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM(2.5) potentiates cardiac remodeling in response to ANG II through RhoA/Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution.
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PMID:Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase. 1928 43

Arginase upregulation is associated with aging and cardiovascular diseases. In this study we report on the cardiovascular phenotype of the arginase II knockout (KO) mouse. We demonstrate that vascular sensitivity and reactivity altered over time in these animals such that no influence on responses to vasoconstrictor activity was observed in 7-week-old KO mice, but dampened responses to norepinephrine and phenylephrine were observed by 10 and 15 weeks with Rho kinase influencing these effects in the 15-week-old animals. Despite these dampened vasoconstrictory responses, KO mice demonstrated increased mean arterial pressure from 8 weeks old. This hypertensive phenotype was associated with an increase in left ventricular weight, left ventricular systolic pressure, and diminished diastolic function. KO mice also show enhanced plasma norepinephrine turnover, suggesting an increased sympathetic outflow. In conclusion, our data suggest that global loss of arginase II activity results in hypertension. We suggest that this strain of mouse warrants further investigation as a potentially novel model of hypertension.
Hypertension 2009 Aug
PMID:Arginase II knockout mouse displays a hypertensive phenotype despite a decreased vasoconstrictory profile. 1954 81

Recent advances in basic and clinical research have identified Rho kinase as an important target potentially implicated in a variety of cardiovascular diseases. Rho kinase is a downstream mediator of RhoA that leads to stress fiber formation, membrane ruffling, smooth muscle contraction, and cell motility. Increased Rho-kinase activity is associated with vasoconstriction and elevated blood pressure. We identified a novel inhibitor of Rho kinase (SAR407899) and characterized its effects in biochemical, cellular, tissue-based, and in vivo assays. SAR407899 is an ATP-competitive Rho-kinase inhibitor, equipotent against human and rat-derived Rho-kinase 2 with inhibition constant values of 36 nM and 41 nM, respectively. It is highly selective in panel of 117 receptor and enzyme targets. SAR407899 is approximately 8-fold more active than fasudil. In vitro, SAR407899 demonstrated concentration-dependent inhibition of Rho-kinase-mediated phosphorylation of myosin phosphatase, thrombin-induced stress fiber formation, platelet-derived growth factor-induced proliferation, and monocyte chemotactic protein-1-stimulated chemotaxis. SAR407899 potently (mean IC(50) values: 122 to 280 nM) and species-independently relaxed precontracted isolated arteries of different species and different vascular beds. In vivo, over the dose range 3 to 30 mg/kg PO, SAR407899 lowered blood pressure in a variety of rodent models of arterial hypertension. The antihypertensive effect of SAR407899 was superior to that of fasudil and Y-27632. In conclusion, SAR407899 is a novel and potent selective Rho-kinase inhibitor with promising antihypertensive activity.
Hypertension 2009 Sep
PMID:Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. 1959 37

Fructose feeding has been shown to induce insulin resistance and hypertension. Renal protein expression for the cytochrome P (CYP) 450 arachidonic acid metabolizing enzymes has been shown to be altered in other models of diet-induced hypertension. Of special interest is CYP4A, which produces the potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid and CYP2C, which catalyzes the formation of the potent dilators epoxyeicosatrienoic acids as well as soluble epoxide hydrolase (sEH) which metabolizes the latter to dihydroxyeicosatrienoic acids. The RhoA/Rho kinase (ROCK) signaling pathway is downstream of arachidonic acid and is reported to mediate metabolic-cardio-renal dysfunctions in some experimental models of insulin resistance and diabetes. The aim of the present study was to determine the expression of CYP4A, CYP2C23, CYP2C11, sEH, RhoA, ROCK-1, ROCK-2, and phospho-Lin-11/Isl-1/Mec-3 kinase (LIMK) in kidneys of fructose-fed (F) rats. Male Wistar rats were fed a high fructose diet for 8 weeks. Body weight, systolic blood pressure, insulin sensitivity, and renal expression of the aforementioned proteins were assessed. No change was observed in the body weight of F rats; however, euglycemia and hyperinsulinemia implicating impaired glucose tolerance and significant elevation in systolic blood pressure were observed. Renal expression of CYP4A and CYP2C23 was significantly increased while that of CYP2C11 and sEH was not changed in F rats. Equal expression for RhoA in both control and F rats and an enhanced level of ROCK-1 and ROCK-2 constitutively activate 130 kDa cleavage fragments as well as phospho-LIMK. These data suggest that the kidneys could be actively participating in the pathogenesis of insulin resistance-induced hypertension through the arachidonic acid CYP 450-RhoA/Rho kinase pathway(s).
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PMID:Renal expression of arachidonic acid metabolizing enzymes and RhoA/Rho kinases in fructose insulin resistant hypertensive rats. 1963 17

Large clinical trials have shown that mineralocorticoid receptor (MR) antagonists improve cardiovascular or total mortality in patients with heart failure or myocardial infarction even though the patients were taking angiotensin-converting enzyme inhibitors or angiotensin II receptor (AT1R) antagonists. We previously reported that cardiac fibrosis induced by aldosterone and salt (Ald-NaCl) was exaggerated in AT1aR knockout mice (AT1aR-KOs). As the association of Rho kinase and oxidative stress was reported in Ald-NaCl-induced hypertension of rats, we investigated the effects of an MR antagonist (eplerenone) and a Rho kinase inhibitor (fasudil) on Ald-NaCl-induced cardiac fibrosis in AT1aR-KOs. AT1aR-KOs were administered aldosterone (0.15 microg/h) subcutaneously using an osmotic minipump and were provided with 1% NaCl drinking water for 4weeks. AT1aR-KOs receiving Ald-NaCl were treated with a low (30 mg/kg/day) or high (100mg/kg/day) dose of eplerenone or a fasudil (100mg/kg/day). Systolic blood pressure (SBP), left ventricular weight/body weight (LVW/BW), histological examination and cardiac gene expression were evaluated on day 28. Ald-NaCl treatment caused increases in SBP and LVW/BW in AT1aR-KOs, and eplerenone dose-dependently decreased SBP, LVW/BW and cardiac fibrosis. Fasudil decreased LVW/BW and cardiac fibrosis without affecting SBP. The expressions of connecting tissue growth factor (CTGF) and nicotinamide adenine dinucleotide phosphate (NADPH) components (p22phox, p47phox and p67phox) were increased in Ald-NaCl-treated AT1aR-KOs, and eplerenone or fasudil decreased the expression of CTGF and NADPH components. Phosphorylated ERM (a marker of the phosphorylation of Rho kinase) was increased in Ald-NaCl-treated AT1aR-KOs and was decreased by eplerenone. Nitrotyrosine and 4-hydroxy-2-nonenal, which indicate tissue damage via oxidative stress, were increased in AT1aR-KO and were apparently attenuated by eplerenone or fasudil. These results suggested that the Rho kinase pathway was activated to induce cardiac fibrosis by Ald-NaCl via MR in AT1aR-KOs. A Rho kinase inhibitor as well as eplerenone might be useful for cardiac damage by Ald-NaCl.
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PMID:Role of Rho kinase and oxidative stress in cardiac fibrosis induced by aldosterone and salt in angiotensin type 1a receptor knockout mice. 1996 25

Hypertensive vasomotor dysfunction is defined by endothelium-dependent contractions involving prostaglandins and ROS. Since both thromboxane-prostanoid receptor (TPr) signaling and ROS activate RhoA-Rho kinase (ROCK) in vascular smooth muscle (VSM) preparations, we hypothesized that enhanced endothelium-dependent contraction in the common carotid artery (CCA) of spontaneously hypertensive rats (SHRs) is ROCK mediated. ACh-stimulated contractions were approximately twofold greater in SHRs versus normotensive Wistar-Kyoto (WKY) rats, abolished by endothelial denudation or cyclooxygenase (COX)-1 inhibition, and nearly eliminated by TPr blockade. RhoA but not ROCK-II protein expression was increased ( approximately 50%) in the SHR CCA. Inhibition of ROCK, but not protein kinase C, caused a dose-dependent reduction in endothelium-dependent contractions to ACh across strains, with the highest dose mirroring the effect of high-dose TPr antagonism. Conversely, ROCK inhibition caused dose-dependent and endothelium- and nitric oxide-independent relaxation in CCAs precontracted with the TPr agonist U-46619. Prostacyclin was the predominant prostaglandin produced by ACh-stimulated CCAs, with greater than twofold more prostacyclin released from SHR versus WKY rats, and its production was unaffected by ROCK inhibition. RhoA activation was approximately twofold higher in quiescent SHR CCAs compared with those from WKY rats and was significantly increased by ACh stimulation. Augmentation of chemical superoxide quenching with tiron or inhibition of the NADPH oxidase-derived superoxide-producing pathway with apocynin reduced ACh-stimulated contractile activity in SHR more than in WKY rats, whereas the SOD mimetic tempol amplified the response. Exposure of CCAs to exogenous H(2)O(2) caused contractions, similar to ACh stimulation, that were greater in SHR than in WKY rats, abolished by COX-1 inhibition, and highly attenuated by TPr blockade or ROCK inhibition. These results indicate that RhoA-ROCK may act as a molecular switch, transducing signals from endothelium-derived prostaglandin(s) and ROS, which are overproduced in SHR CCAs, to "turn on" VSM contractile pathways, thus mediating the enhanced endothelium- and endoperoxide-dependent vascular contractions characteristic of hypertension, among other cardiovascular disease states, such as diabetes and aging.
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PMID:RhoA-Rho kinase signaling mediates endothelium- and endoperoxide-dependent contractile activities characteristic of hypertensive vascular dysfunction. 2015 58

Rho kinase-mediated vasoconstriction rather than fixed arterial wall thickening is responsible for increased pulmonary vascular resistance and pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. In the absence of vascular tone, the medial and adventitial thickening in these models has only minimal impact on the cross-sectional area of the pulmonary arterial bed. In contrast, increased pulmonary vascular resistance in left-pneumonectomized plus monocrotaline-injected rats and VEGF receptor blocker-injected plus chronic hypoxia rats is attributable to both Rho kinase-mediated vasoconstriction and formation of lumen obliterating lesions in small pulmonary arteries. The upstream signals responsible for activation of RhoA/Rho kinase signaling in hypertensive pulmonary arteries and whether or not they differ in different forms of pulmonary hypertension are unclear. The RhoA/Rho kinase pathway is a convergence point of several different vasoconstrictor signals, including those mediated by G protein-coupled receptors, receptor tyrosine kinases, and integrin clustering. Both isoforms of Rho kinase can also be constitutively activated by cleavage, and cleaved Rho kinase 1 has been detected in the hypertensive lungs of left-pneumonectomized plus monocrotaline-injected rats. That such diverse stimuli can lead to activation of Rho kinase, which may cause hypercontraction of smooth muscle by promoting both actomyosin interaction and remodeling of the cytoskeleton, may explain why in various rat models of pulmonary hypertension Rho kinase inhibitors are more effective pulmonary vasodilators than conventional agents such as nitric oxide, prostacyclin, and nifedipine. We suspect the same will be true in at least some forms of human pulmonary arterial hypertension.
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PMID:Rho kinase-mediated vasoconstriction in pulmonary hypertension. 2020 38

Current treatment of pulmonary arterial hypertension, which includes the use of prostacyclins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, either alone or in combination, often leads to improvements in functional capacity and modest decreases in pulmonary artery pressure. Disappointingly, however, two recent meta-analysis reviewing the controlled trials in pulmonary arterial hypertension, using these three agents, demonstrated little or no increase in survival. Importantly, however, increasing knowledge of the cellular and molecular basis of pulmonary arterial hypertension has led to the development of new agents aimed at either reversing sustained vasoconstriction or stopping/reversing the abnormal cell and extracellular matrix accumulation that, in combination, obstruct pulmonary blood flow and ultimately cause right heart failure. Rho kinase inhibitors, vasodilator peptides (such as vasoactive intestinal peptide and adrenomedullin), and endothelial nitric oxide synthase coupling agents (cicletanine) have been shown sometimes to exert potent pulmonary vasodilatory effects in animal models and in pilot studies in humans. Tyrosine kinase inhibitors (platelet-derived growth factor and epidermal growth factor receptor inhibitors), multikinase inhibitors (tyrosine kinase and serine/threonine kinase), elastase inhibitors, metabolic modulators (e.g., dichloroacetate), survivin inhibitors, and HMG-COA reductase inhibitors have been shown to reverse pulmonary hypertension in rodent models of pulmonary hypertension through inhibition of cell proliferation and induction of apoptosis. Early success in human pulmonary arterial hypertension with tyrosine kinase inhibitors has appeared in case reports. Furthermore, anti-inflammatory/immunomodulatory agents (thiazolidinedinones, rapamycin, cyclosporine, and STAT3 inhibitors) have been demonstrated to be effective at reducing vascular remodeling in animal models. Collectively, these studies are exciting and open potential new avenues for treatment. Caution should be exercised, however, as many agents, which are successful at preventing or reversing pulmonary arterial hypertension in currently used animal models, do not result in similar long-term success in the treatment of human pulmonary arterial hypertension.
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PMID:Emerging therapies for the treatment of pulmonary hypertension. 2021 70


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