Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported enhanced expression of the p67(phox) and gp91(phox) components of NAD(P)H oxidase in angiotensin (Ang) II-induced hypertension, suggesting de novo assembly in response to Ang II. To examine the direct involvement of NAD(P)H oxidases in Ang II-induced O(2)(-) production, we designed a chimeric peptide that inhibits p47(phox) association with gp91(phox) in NAD(P)H oxidase (gp91ds-tat). This was achieved by linking a 9-amino acid peptide (aa) derived from HIV-coat protein (tat) to a 9-aa sequence of gp91(phox) (known to interact with p47(phox)). As a control, we constructed a chimera containing tat and a scrambled gp91 sequence (scramb-tat). We found that gp91ds-tat decreased O(2)(-) levels in aortic rings treated with Ang II (10 pmol/L) but had no effect on either the O(2)(-)-generating enzyme xanthine oxidase or potassium superoxide-generated O(2)(-). We infused vehicle, Ang II (0.75 mg. kg(-1). d(-1)), Ang II+gp91ds-tat (10 mg. kg(-1). d(-1)), or Ang II+scramb-tat intraperitoneally in C57Bl/6 mice and measured systolic blood pressure (SBP) on days 0, 3, 5, and 7 of infusion. SBP increased by day 3 in mice given Ang II and Ang II+scramb-tat but was significantly lower with Ang II+gp91-tat. On day 7, SBP was still significantly inhibited in mice given Ang II+gp91ds-tat, whereas Ang II-induced O(2)(-) production was inhibited throughout the aorta as detected by dihydroethidium staining, consistent with the ability of this inhibitor to block the various vascular NAD(P)H oxidase isoforms. These data support the hypothesis that inhibition of the interaction of p47(phox) and gp91(phox) (or its homologues) can block O(2)(-) production and attenuate blood pressure elevation in mice.
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PMID:Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. 1153 1

Angiotensin II (Ang II) exerts detrimental effects on cerebral circulation, the mechanisms of which have not been elucidated. In particular, Ang II impairs the increase in cerebral blood flow (CBF) produced by neural activity, a critical mechanism that matches substrate delivery with energy demands in brain. We investigated whether Ang II exerts its deleterious actions by activating Ang II type 1 (AT1) receptors on cerebral blood vessels and producing reactive oxygen species (ROS) through NADPH oxidase. Somatosensory cortex CBF was monitored in anesthetized mice by laser-Doppler flowmetry. Ang II (0.25 microg/kg per minute IV) attenuated the CBF increase produced by mechanical stimulation of the vibrissae. The effect was blocked by the AT1 antagonist losartan and by ROS scavenger superoxide dismutase or tiron and was not observed in mice lacking the gp91phox subunit of NADPH oxidase or in wild-type mice treated with the NADPH oxidase peptide inhibitor gp91ds-tat. Ang II increased ROS production in cerebral microvessels, an effect blocked by the ROS scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin and by the NADPH oxidase assembly inhibitor apocynin. Ang II did not increase ROS production in gp91-null mice. Double-label immunoelectron microscopy demonstrated that AT1 and gp91phox immunoreactivities were present in endothelium and adventitia of neocortical arterioles. Collectively, these findings suggest that Ang II impairs functional hyperemia by activating AT1 receptors and inducing ROS production via a gp91phox containing NADPH oxidase. The data provide the mechanistic basis for the cerebrovascular dysregulation induced by Ang II and suggest novel therapeutic strategies to counteract the effects of hypertension on the brain.
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PMID:Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. 1549 27

The role of soluble epoxide hydrolase (sEH) in the central control of blood pressure (BP) has not been elucidated in spite of peripheral sEH overexpression being linked to hypertension. Thus, our objective was to investigate the involvement of brain sEH in BP control. sEH expression in the hypothalamus and brain stem, two cardioregulatory brain areas, was increased in the spontaneously hypertensive rat (SHR) compared to the Wistar Kyoto (WKY) rat. Inhibition of the enzyme by intracerebroventricular (icv) delivery of AUDA further increased both BP and heart rate (HR) by 32 +/- 6 mmHg and 54 +/- 10 bpm, respectively, (P<0.05) in the SHR. Analysis of waveform telemetry data revealed a decrease in spontaneous baroreceptor reflex gain following sEH inhibition, indicating the sustained increase in BP may be due to a decrease in baroreceptor reflex function. The hypertensive effect of sEH inhibition is likely a result of an increase in epoxyeicosatrienoic acid (EET)-mediated generation of ROS. This view is supported by the following: 1) Inhibition of EET formation attenuates AUDA-induced increase in BP; 2) delivery of an EET agonist increases BP and HR in the WKY rat, and 3) inhibition of NAD(P)H oxidase by gp91ds-tat prevents AUDA-induced increases in BP and HR. Finally, electrophysiological studies demonstrate that AUDA increased neuronal firing rate exclusively in the SHR, an effect completely abolished by gp91ds-tat. These observations suggest that EETs and sEH inhibition are involved in increasing BP in the SHR. We suggest that an increased expression of sEH is a futile central nervous system response in protection against hypertension.
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PMID:Novel mechanism of brain soluble epoxide hydrolase-mediated blood pressure regulation in the spontaneously hypertensive rat. 1565 36

Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase-derived reactive oxygen species (ROS), plays a critical role in ED. gp91phox, predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91phox. We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47phox with gp91phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168+/-5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159+/-5 mm Hg; P>0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.
Hypertension 2006 Jan
PMID:Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. 1634 66

The dorsomedial portion of the nucleus tractus solitarius (dmNTS) is the site of termination of baroreceptor and cardiorespiratory vagal afferents and plays a critical role in cardiovascular regulation. Angiotensin II (Ang II) is a powerful signaling molecule in dmNTS neurons and exerts some of its biological effects by modulating Ca(2+) currents via reactive oxygen species (ROS) derived from reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. We investigated whether a Nox2-containing NADPH oxidase is the source of the Ang II-induced ROS production and whether the signaling mechanisms of its activation require intracellular Ca(2+) or protein kinase C (PKC). Second-order dmNTS neurons were anterogradely labeled with 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide transported from the vagus and isolated from the brain stem. ROS production was assessed in 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide-positive dmNTS neurons using the fluorescent dye 6-carboxy-2',7'-dichlorodihydro-fluorescein di(acetoxymethyl ester). Ang II (3 to 2000 nmol/L) increased ROS production in dmNTS neurons (EC(50)=38.3 nmol/L). The effect was abolished by the ROS scavenger Mn (III) porphyrin 5,10,20-tetrakis (benzoic acid) porphyrin manganese (III), the Ang II type 1 receptor antagonist losartan, or the NADPH oxidase inhibitors apocynin or gp91ds-tat. Ang II failed to increase ROS production or to potentiate L-type Ca(2+) currents in dmNTS neurons of mice lacking Nox2. The PKC inhibitor GF109203X or depletion of intracellular Ca(2+) attenuated Ang II-elicited ROS production. We conclude that the powerful effects of Ang II on Ca(2+) currents in dmNTS neurons are mediated by PKC activation leading to ROS production via Nox2. Thus, a Nox2-containing NADPH oxidase is the critical link between Ang II and the enhancement of Ca(2+) currents that underlie the actions of Ang II on central autonomic regulation.
Hypertension 2006 Sep
PMID:Nox2, Ca2+, and protein kinase C play a role in angiotensin II-induced free radical production in nucleus tractus solitarius. 1689 58

Endothelial dysfunction precedes hypertension and atherosclerosis and predicts cardiac allograft vasculopathy and death in heart transplant recipients. Endothelial overproduction of reactive oxygen species, such as superoxide anions produced by NAD(P)H oxidase, induces endothelial dysfunction. Because immunosuppressive drugs have been associated with increased reactive oxygen species production and endothelial dysfunction, we sought to elucidate the underlying mechanisms. Reactive oxygen species, release of superoxide anions, and NAD(P)H oxidase activity were studied in human umbilical vein endothelial cells and in polymorphonuclear neutrophils. Gp91ds-tat was used to specifically block NAD(P)H oxidase. Transcriptional activation of different subunits of NAD(P)H oxidase was assessed by real-time RT-PCR. Rac1 subunit translocation and activation were studied by membrane fractionation and pull-down assays. Calcineurin inhibitors significantly increased endothelial superoxide anions production because of NAD(P)H oxidase, whereas mycophenolate acid (MPA) blocked it. MPA also attenuated the respiratory burst induced by neutrophil NAD(P)H oxidase. Because transcriptional activation of NAD(P)H oxidase was not affected, but addition of guanosine restored endothelial superoxide anions formation after MPA treatment, we speculate that the inhibitory effect of MPA was mediated by depletion of cellular guanosine triphosphate content. This prevented activation of Rac1 and, thus, of endothelial NAD(P)H oxidase. Because all heart transplant recipients are at risk for cardiac allograft vasculopathy development, these differential effects of immunosuppressants on endothelial oxidative stress should be considered in the choice of immunosuppressive drugs.
Hypertension 2007 Jan
PMID:Mycophenolate acid inhibits endothelial NAD(P)H oxidase activity and superoxide formation by a Rac1-dependent mechanism. 1710 43

NADPH oxidases have recently been shown to contribute to the pathogenesis of hypertension. The development of specific inhibitors of these enzymes has focused attention on their potential therapeutic use in hypertensive disease. Two of the most specific inhibitors, gp91ds-tat and apocynin, have been shown to decrease blood pressure in animal models of hypertension. Other inhibitors, including diphenylene iodonium, aminoethyl benzenesulfono fluoride, S17834, PR39, protein kinase C inhibitors, and VAS2870, have shown promise in vitro, but their in vivo specificity, pharmacokinetics, and effectiveness in hypertension remains to be determined. Of importance, the currently available antihypertensive agents angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also effectively inhibit NADPH oxidase activation. Similarly, the cholesterol-lowering agents, statins, have been shown to attenuate NADPH oxidase activation. Although, antioxidants act to scavenge the reactive oxygen species produced by these enzymes, their effectiveness is limited. Targeting NADPH homologues may have a distinct advantage over current therapies because it would specifically prevent the pathophysiological formation of reactive oxygen species that contributes to hypertension.
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PMID:NADPH oxidase inhibitors: new antihypertensive agents? 1766 10

Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important for its major role in insulin-mediated glucose disposal. Angiotensin II (ANG II) is integral in regulating blood pressure and plays a role in the pathogenesis of hypertension. In addition, we have documented that ANG II-induced skeletal muscle insulin resistance is associated with generation of reactive oxygen species (ROS). However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren-2) hypertensive rat, which harbors the mouse renin transgene and exhibits elevated tissue ANG II levels, and skeletal muscle cell culture. Compared with Sprague-Dawley normotensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-kappaB activation, and TNF-alpha expression, which were attenuated by in vivo treatment with an angiotensin type 1 receptor blocker (valsartan) or SOD/catalase mimetic (tempol). Moreover, ANG II treatment of L6 myotubes induced NF-kappaB activation and TNF-alpha production and decreased insulin-stimulated Akt activation and GLUT-4 glucose transporter translocation to plasma membranes. These effects were markedly diminished by treatment of myotubes with valsartan, the antioxidant N-acetylcysteine, NADPH oxidase-inhibiting peptide (gp91 ds-tat), or NF-kappaB inhibitor (MG-132). Similarly, NF-kappaB p65 small interfering RNA reduced NF-kappaB p65 subunit expression and nuclear translocation and TNF-alpha production but improved insulin-stimulated phosphorylation (Ser(473)) of Akt and translocation of GLUT-4. These findings suggest that NF-kappaB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.
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PMID:Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. 1807 21

Alpha(2)-adrenoceptors potentiate renal vascular responses to angiotensin II via coincident signaling at phospholipase C. This leads to increased activation of the phospholipase C/protein kinase C/c-src pathway. Studies suggest that c-src activates the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase/superoxide system, and reactive oxygen species stimulate the RhoA/Rho kinase pathway. Therefore, we hypothesized that NADPH oxidase/superoxide and RhoA/Rho kinase are downstream components of the signal transduction pathway that mediate the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance. In rat kidneys, both in vivo and in vitro, intrarenal infusions of angiotensin II increased renal vascular resistance, and UK14,304 (alpha(2)-adrenoceptor agonist) enhanced this response. Intrarenal Tempol (superoxide dismutase mimetic) or Y27632 (Rho kinase inhibitor) abolished the interaction between UK14,304 and angiotensin II both in vivo and in vitro. The interaction was also blocked by inhibitors of NADPH oxidase (in vivo using chronic gp91ds-tat administration and in vitro with diphenyleneiodonium). In cultured preglomerular vascular smooth muscle cells, UK14,304 enhanced angiotensin II-induced intracellular superoxide (2-hydroxyethidium production) and potentiated activation of RhoA (Western blot of activated RhoA bound to the binding domain of rhotekin). The interaction between angiotensin II and UK14,304 on superoxide generation and RhoA activation was blocked by inhibitors of phospholipase C (U73312), protein kinase C (GF109203X), c-src (PP1), NADPH oxidase (diphenyleneiodonium), or superoxide (Tempol). We conclude that NADPH oxidase/superoxide and RhoA/Rho kinase are involved in the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance by mediating signaling events downstream of the phospholipase C/protein kinase C/c-src pathway.
Hypertension 2008 Mar
PMID:Alpha2-adrenoceptors enhance angiotensin II-induced renal vasoconstriction: role for NADPH oxidase and RhoA. 1825 Mar 67

Spontaneously hypertensive rats (SHRs) have normal glomerular capillary pressure even though renal perfusion pressure is higher, suggesting that preglomerular vessels exhibit abnormally high resistance. This may be due to increased superoxide (O(2)(-)) production, which contributes to the vasoconstriction in hypertension. We tested the hypothesis that the myogenic response of the afferent arteriole (Af-Art) is exaggerated in SHRs because of increased levels of reactive oxygen species (ROS). Single Af-Arts were microdissected from kidneys of SHRs and Wistar-Kyoto (WKY) rats and microperfused in vitro. When perfusion pressure in the Af-Art was increased stepwise from 60 to 140 mmHg, the luminal diameter decreased by 8.4 + or - 2.9% in WKY Af-Arts but fell by 29.3 + or - 5.6% in SHR Af-Arts. To test whether ROS production is enhanced during myogenic response in SHRs, we measured chloromethyl-dichlorodihydrofluorescein diacetate acetyl ester (CM-H(2)DCFDA) florescence before and after increasing intraluminal pressure from 60 to 140 mmHg. Pressure-induced increases in ROS were fourfold greater in SHR Af-Arts compared with WKY Af-Arts (SHR, 48.0 + or - 2.2%; and WKY, 12.2 + or - 0.3%). To test whether O(2)(-) contributes to the myogenic response in SHRs, either the membrane-permeant O(2)(-) scavenger Tempol or the nox2-based NADPH oxidase (NOX2) inhibitor gp91ds-tat were added to the Af-Art lumen and bath and the myogenic response was tested before and after treatment. Both Tempol (10(-4) M) and gp91ds-tat (10(-5) M) significantly attenuated the pressure-induced constriction in SHR Af-Arts but not in WKY Af-Arts. We conclude that 1) pressure-induced constriction is exaggerated in SHR Af-Arts, 2) NOX2-derived O(2)(-) may contribute to the enhanced myogenic response, and 3) O(2)(-) exerts little influence on the myogenic response under normotensive conditions.
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PMID:Enhanced myogenic response in the afferent arteriole of spontaneously hypertensive rats. 2036 86


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