UMLS:C0020538 - FACTA Search

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

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. The components of the RAS including renin, angiotensin-converting enzyme, and angiotensin receptors are expressed throughout the body in tissues that may impact blood pressure control. Blocking actions of individual components of the RAS including renin, angiotensin-converting enzyme, or the type 1 (AT(1)) receptor lowers blood pressure. Although it has been suggested that control of sodium excretion by the kidney is the dominant mechanism for blood pressure regulation by the RAS, pharmacologic antagonists or conventional gene-targeting experiments globally interrupt the RAS and cannot discriminate its actions in the kidney from other tissue compartments. Recent experiments with the use of kidney cross-transplantation and genetically engineered mice suggest independent and equivalent effects of angiotensin II acting via AT(1) receptors in the kidney and in extrarenal tissues to maintain the normal level of blood pressure. However, the nature and relative contributions of these actions may differ in hypertension.
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PMID:AT(1) receptors and control of blood pressure: the kidney and more... 1721 Apr 76

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Components of the RAS, including renin, angiotensin-converting enzyme (ACE), and angiotensin type 1 (AT1) receptors, are expressed throughout the body in tissues that may impact blood pressure control. Blocking actions of individual components of the RAS lowers blood pressure. Although it has been suggested that control of sodium excretion by the kidney is the dominant mechanism for blood pressure regulation by the RAS, pharmacologic antagonists or conventional gene targeting experiments globally interrupt the RAS and cannot discriminate its actions in the kidney from other tissue compartments. Recent experiments using kidney cross-transplantation and genetically engineered mice have confirmed a major role for angiotensin II acting via AT1 receptors in the kidney in hypertension. These actions of renal AT1 receptors are required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. These findings, with previous experiments, clearly establish the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications.
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PMID:In hypertension, the kidney rules. 1744 27

Epoxyeicosatrienoic acids (EETs), as metabolites of arachidonic acid, may function as antihypertensive and antiatherosclerotic mediators for vasculature. EETs are degraded by soluble epoxide hydrolase (sEH). Pharmacological inhibition and genetic ablation of sEH have been shown to increase the level of EETs, and treating angiotensin II (Ang II)-infused hypertension rats with sEH-selective inhibitors increased the levels of EETs, with attendant decrease in systolic blood pressure. To elucidate the mechanisms by which Ang II regulates sEH expression, we treated human umbilical vein endothelial cells (ECs) and bovine aortic ECs with Ang II and found increased sEH expression at both the mRNA and protein levels. Transient transfection assays showed that the activity of the human sEH promoter was increased in ECs in response to Ang II. Further analysis of the promoter region of the sEH gene demonstrated that treatment with Ang II, like overexpression of c-Jun/c-Fos, activates the sEH promoter through an AP-1-binding motif. The binding of c-Jun to the AP-1 site of the sEH promoter was confirmed by chromatin immunoprecipitation assays. In contrast, adenovirus overexpression of the dominant-negative mutant of c-Jun significantly attenuated the effects of Ang II on sEH induction. An elevated level of sEH was found in the aortic intima of both spontaneously hypertensive rats and Ang II-infused Wistar rats. Blocking Ang II binding to Ang II receptor 1 by losartan abolished the sEH induction. Thus, AP-1 activation is involved in the transcriptional up-regulation of sEH by Ang II in ECs, which may contribute to Ang II-induced hypertension.
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PMID:Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. 1749 27

Polycystic kidney diseases (autosomal dominant and autosomal recessive) are progressive renal tubular cystic diseases, which are characterised by cyst expansion and loss of normal kidney structure and function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common life- threatening, hereditary disease. ADPKD is more prevalent than Huntington's disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down's syndrome combined. Early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and its potential protective effect on left ventricular hypertrophy has been one of the major therapeutic goals to decrease cardiac complications and contribute to improved prognosis of the disease. Advances in the understanding of the genetics, molecular biology and pathophysiology of the disease are likely to facilitate the improvement of treatments for these diseases. Developments in describing the role of intracellular calcium ([Ca(2+)](i)) and its correlation with cellular signalling systems, Ras/Raf/mitogen extracellular kinase (MEK)/extracellular signal-regulated protein kinase (ERK), and interaction of these pathways with cyclic adenosine monophosphate (cAMP) levels, provide new insights on treatment strategies. Blocking the vasopressin V(2) receptor, a major adenylyl cyclase agonist, demonstrated significant improvements in inhibiting cytogenesis in animal models. Because of activation of the mammalian target of rapamycin (mTOR) pathway, the use of sirolimus (rapamycin) an mTOR inhibitor, markedly reduced cyst formation and decreased polycystic kidney size in several animal models. Caspase inhibitors have been shown to decrease cytogenesis and renal failure in rats with cystic disease. Cystic fluid secretion results in cyst enlargement and somatostatin analogues have been shown to decrease renal cyst progression in patients with ADPKD. The safety and efficacy of these classes of drugs provide potential interventions for experimental and clinical trials.
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PMID:Potential pharmacological interventions in polycystic kidney disease. 1803 88

RGS5 is a potent GTPase-activating protein for G(ialpha) and G(qalpha) that is expressed strongly in pericytes and is present in vascular smooth muscle cells. To study the role of RGS5 in blood vessel physiology, we generated Rgs5-deficient mice. The Rgs5(-/-) mice developed normally, without obvious defects in cardiovascular development or function. Surprisingly, Rgs5(-/-) mice had persistently low blood pressure, lower in female mice than in male mice, without concomitant cardiac dysfunction, and a lean body habitus. The examination of the major blood vessels revealed that the aortas of Rgs5(-/-) mice were dilated compared to those of control mice, without altered wall thickness. Isolated aortic smooth muscle cells from the Rgs5(-/-) mice exhibited exaggerated levels of phosphorylation of vasodilator-stimulated phosphoprotein and extracellular signal-regulated kinase in response to stimulation with either sodium nitroprusside or sphingosine 1-phosphate. The results of this study, along with those of previous studies demonstrating that RGS5 stability is under the control of nitric oxide via the N-end rule pathway, suggest that RGS5 may balance vascular tone by attenuating vasodilatory signaling in vivo in opposition to RGS2, another RGS (regulator of G protein signaling) family member known to inhibit G protein-coupled receptor-mediated vasoconstrictor signaling. Blocking the function or the expression of RGS5 may provide an alternative approach to treat hypertension.
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PMID:Rgs5 targeting leads to chronic low blood pressure and a lean body habitus. 1826 11

Our current understanding of the pathophysiology of atherosclerosis suggests a prominent role for immune responses from its initiation through its complications. Given the increasing prevalence of cardiovascular risk factors worldwide, there is an urgent need to better understand the underlying mechanisms to improve current treatment protocols. A growing body of evidence suggests that endocannabinoid signalling plays a critical role in the pathogenesis of atherogenesis and its clinical manifestations. Blocking CB(1) receptors has been shown to mediate not only weight reduction, but also several cardiometabolic effects in rodents and humans, indicating a potential relevance for the process of atherosclerosis. Activation of CB(2) receptors with Delta(9)-tetrahydrocannabinol (THC) has been shown to inhibit atherosclerotic plaque progression in mice, mainly by inhibiting macrophage recruitment. Endocannabinoids released from endothelial cells, macrophages or platelets, reduce hypertension in rodents, a major risk factor for atherosclerosis. In addition, anandamide inhibits inflammatory gene expression in endothelial cells, and consequently monocyte adhesion. Conversely, endocannabinoids might also mediate pro-atherosclerotic effects by inducing platelet activation. In conclusion, the precise role of the endocannabinoid system during atherosclerosis is not yet understood. Whether increased endocannabinoid signalling is associated with disease progression and increased risk of acute thrombotic events remains to be determined.
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PMID:The role of the endocannabinoid system in atherosclerosis. 1842

Diabetes and insulin resistance are associated with an increased risk of hypertension and cardiovascular disease. Recent evidence demonstrates that AT2 receptors (AT2R) play an important role in the hemodynamic control of hypertension by vasodilation. The quantitative significance of AT2R in the establishment of diabetic vascular dysfunction, however, is not well defined and needs further investigation. Goto-Kakizaki (GK) rats, a polygenic model of spontaneous normotensive type 2 diabetes, were used to examine any abnormalities in cardiovascular function associated with AT2R at the early stage of the disease without endothelium influence. Using a myograph to measure the isometric force, we observed that ANG II-induced contraction was impaired in denuded GK aorta compared with control Wistar-Kyoto (WKY) aorta and exhibited a retarded AT1R antagonist response and enhanced Rho kinase signaling. When AT1R were blocked, ANG II induced a significant vasodilation of precontracted GK aorta via AT2R. The protein and mRNA of AT2R were increased in diabetic GK denuded aorta. Blocking AT2R restored the ANG II-induced contraction in the GK vasculature to control levels, demonstrating a counteractive role for AT2R in AT1R-induced contraction. Inhibition of inducible nitric oxide synthase (iNOS) by NG-monomethyl-L-arginine mimicked AT2R inhibition in denuded GK aorta, suggesting that AT2R-induced vasodilation was dependent on iNOS/NO generation. The protein and mRNA of iNOS were also increased in GK aorta. In conclusion, these results clearly demonstrate that enhanced AT2R and iNOS-induced, NO-mediated vasodilation impair ANG II-induced contraction in an endothelium-independent manner at the early stage of type 2 diabetes.
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PMID:Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats. 1846 92

GABA(B) receptor function is upregulated in the paraventricular nucleus (PVN) of the hypothalamus in spontaneously hypertensive rats (SHR), but it is unclear whether this upregulation occurs pre- or postsynaptically. We therefore determined pre- and postsynaptic GABA(B) receptor function in retrogradely labeled spinally projecting PVN neurons using whole cell patch-clamp recording in brain slices in SHR and Wistar-Kyoto (WKY) rats. Bath application of the GABA(B) receptor agonist baclofen significantly decreased the spontaneous firing activity of labeled PVN neurons in both SHR and WKY rats. However, the magnitude of reduction in the firing rate was significantly greater in SHR than in WKY rats. Furthermore, baclofen produced larger membrane hyperpolarization and outward currents in labeled PVN neurons in SHR than in WKY rats. The baclofen-induced current was abolished by either including G protein inhibitor GDPbetaS in the pipette solution or bath application of the GABA(B) receptor antagonist in both SHR and WKY rats. Blocking N-methyl-d-aspartic acid receptors had no significant effect on baclofen-elicited outward currents in SHR. In addition, baclofen caused significantly greater inhibition of glutamatergic excitatory postsynaptic currents (EPSCs) in labeled PVN neurons in brain slices from SHR than WKY rats. By contrast, baclofen produced significantly less inhibition of GABAergic inhibitory postsynaptic currents (IPSCs) in labeled PVN neurons in SHR than in WKY rats. Although microinjection of the GABA(B) antagonist into the PVN increases sympathetic vasomotor tone in SHR, the GABA(B) antagonist did not affect EPSCs and IPSCs of the PVN neurons in vitro. These findings suggest that postsynaptic GABA(B) receptor function is upregulated in PVN presympathetic neurons in SHR. Whereas presynaptic GABA(B) receptor control of glutamatergic synaptic inputs is enhanced, presynaptic GABA(B) receptor control of GABAergic inputs in the PVN is attenuated in SHR. Changes in both pre- and postsynaptic GABA(B) receptors in the PVN may contribute to the control of sympathetic outflow in hypertension.
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PMID:Plasticity of pre- and postsynaptic GABAB receptor function in the paraventricular nucleus in spontaneously hypertensive rats. 1856 9

Although the awareness and control of hypertension has increased, only 37% of hypertensive patients in the US achieve the conservative goal of <140/90 mmHg. Achieving optimal blood pressure (BP) control is the most important single issue in the management of hypertension, and in most hypertensive patients, it is difficult or impossible to control BP with one drug. Blocking two or more BP regulatory systems provides a more effective and more physiologic reduction in BP, and current guidelines have recommended the use of combination therapy as first-line treatment, or early in the management of hypertension. Fixed combination therapy is an efficacious, relatively safe, and may be cost-effective method of decreasing BP in most patients with essential hypertension. Similar to other combinations, fixed-dose combination tablets containing the dihydropyridine calcium channel blocker amlodipine and the angiotensin II receptor blocker olmesartan bring together two distinct and complementary mechanisms of action, resulting in improved BP control and potential for improved target organ protection relative to either class of agent alone.
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PMID:Fixed combinations in the management of hypertension: patient perspectives and rationale for development and utility of the olmesartan-amlodipine combination. 1882 15

Hypertension is a highly prevalent disease and one of the most important modifiable risk factors for cardiovascular disease. Hypertension remains the leading cause of mortality and the third largest cause of disability in both developed and developing countries. Although recent guidelines and advisory statements are recommending lower thresholds and goals for antihypertensive treatment, approximately two thirds of patients do not achieve the goals. In the United States only 36.8% of hypertensive patients achieve the goal of <140/90 mmHg. Poor adherence to antihypertensive medication regimens contributes to the practice-outcome gap. In most hypertensive patients it is difficult or impossible to control blood pressure with one drug, thus current guidelines have recommended the use of combination therapy as first-line treatment, or early in the management of hypertension. Blocking two or more blood pressure regulatory systems provides a more effective and more physiologic reduction in blood pressure. Fixed-dose combinations offer many advantages over free-drug combinations, such as convenience of use, fewer adverse events, and greater antihypertensive potency. Similar to other combinations, fixed-dose combination tablets containing the dihydropyridine calcium channel blocker amlodipine and the angiotensin receptor blocker olmesartan bring together two distinct and complementary mechanisms of action, resulting in improved blood pressure control and potential for improved target organ protection relative to either class of agent alone.
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PMID:Olmesartan/Amlodipine: combination therapy for the treatment of hypertension [corrected]. 1912 98

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