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

Arginase catalyzes the hydrolysis of arginine to urea and ornithine. Urea is not only an important solute for concentrating urine but also inhibits Na-K-2Cl cotransport. To elucidate the roles of arginase in the development of salt-sensitive hypertension, we examined arginase activity and expression in the kidney and other organs of Dahl/Rapp salt-sensitive (SS) and salt-resistant (SR) rats before and after 4 weeks' administration of a 4% NaCl or control diet. At 4 weeks of age, arginase activity in the kidney was lower in SS rats than in SR rats. Kidney arginase activity was lower in SS rats than in SR rats at 8 weeks of age, and salt loading did not alter arginase activity. Arginase II (the dominant isoform in the kidney) mRNA and protein in the kidney of salt-loaded SS rats were also lower than those of salt-loaded SR rats. Arginase activities in the liver and cerebellum did not differ between SS and SR rats. To examine the effect of urea, the product of arginase reaction, on the development of hypertension, SS rats were given a 4% NaCl diet containing 5% kaolin or 5% urea. Six-week urea supplementation attenuated the development of hypertension in SS rats. These findings suggest that decreased arginase expression in the kidney may be at least partially responsible for the salt-sensitive hypertension in SS rats.
 ...
PMID:Decreased expression of arginase II in the kidneys of Dahl salt-sensitive rats. 1213 20

Increased intracranial pressure (ICP) in patients with acute liver failure (ALF) remains a major cause of morbidity and mortality. Conventional methods of ammonia reduction such as the use of lactulose do not improve outcome, and metabolic substrates such as L-ornithine L aspartate may offer more promise. Mannitol remains the mainstay of therapy. An important role for cerebral hyperemia in the pathogenesis of increased ICP has led to a reevaluation of established therapies such as hyperventilation, N-acetylcysteine, thiopentone sodium, and propofol. Recent studies have focused on the role of systemic inflammatory response in the pathogenesis of increased ICP and support the use of antibiotics prophylactically. Moderate hypothermia reduces ICP in patients with uncontrolled intracranial hypertension and prevents increases in ICP during orthotopic liver transplantation (OLT). Advances in understanding the pathophysiological basis of intracranial hypertension in ALF have outstripped appropriate testing of the newly generated ideas in appropriate clinical trials, and more effort should be mounted at a national level to organize the appropriate multicenter studies required.
 ...
PMID:Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. 1452 80

Less nitric oxide (NO)-dependent vasodilation and excess formation of reactive oxygen species could explain poor placenta perfusion in preeclampsia, but the pathways involved are unknown. We tested the hypothesis that reduced NO activity and increased oxidative stress in preeclamptic placenta is related to a low bioavailability of l-arginine. Placental endothelial NO synthase (ecNOS) expression (by immunoperoxidase) and activity (by diaphorase and [(3)H]L-citrulline formation) were comparable in normotensive pregnancy and in preeclampsia, whereas nitrotyrosine staining, a marker of peroxynitrite, was stronger in preeclamptic villi, confirming previously reported data. Oxidative tissue damage was documented in preeclamptic villi by strong 4-hydroxynonenal-lysine staining (by immunoperoxidase), which closely colocalized with nitrotyrosine. Concentration of the NO precursor l-arginine (by HPLC) in umbilical blood and in villous tissue was lower in preeclampsia than in normotensive pregnancy. This was not caused by a defective l-arginine transport, because gene expression of the CAT-1, 4F2hc, and LAT-1 cationic amino acid transporters (by real-time reverse-transcription polymerase chain reaction [RT-PCR]) was normal. Instead, gene expression (by real-time RT-PCR) and protein tissue content (by immunoperoxidase and Western blot) of arginase II-the enzyme that degrades arginine to ornithine-were higher in preeclamptic villi than in normotensive pregnancy. These results provide a biochemical explanation for defective NO activity and increased oxidative stress in preeclamptic placenta. In normal placenta, adequate concentration of l-arginine orients ecNOS toward NO. In preeclampsia, a lower than normal l-arginine concentration caused by arginase II overexpression redirects ecNOS toward peroxynitrite.
Hypertension 2004 Mar
PMID:L-arginine depletion in preeclampsia orients nitric oxide synthase toward oxidant species. 1521 85

Vascular tissues express arginase that metabolizes L-arginine to L-ornithine and urea and thus reduces substrate availability for nitric oxide formation. Dahl salt-sensitive (Dahl-S) rats with salt-induced hypertension show endothelial dysfunction, including decreased vascular nitric oxide formation. This study tests the hypothesis that increased vascular arginase activity contributes to endothelial dysfunction in hypertensive Dahl-S rats. Male Dahl-S rats (5-6 wk) were placed on high (8%) or low (0.3%) NaCl diets for 4 wk. With respect to the low-salt group, mean arterial blood pressure was increased in the high-salt animals. Immunohistochemical stainings for arginase I and II were enhanced in arterioles isolated from high-salt Dahl-S rats. Experiments used isolated Krebs buffer-superfused first-order gracilis muscle arterioles with constant pressure (80 mmHg) and no luminal flow or constant midpoint but altered endpoint pressures to establish graded levels of luminal flow (0-50 microl/min). In high-salt arterioles, responses to an endothelium-dependent vasodilator acetylcholine (1 nmol/l to 3 micromol/l) and flow-induced dilation were decreased. Acute in vitro treatment with an inhibitor of arginase, 100 micromol/l (S)-(2-boronoethyl)-L-cystine, or the nitric oxide precursor, 1 mmol/l L-arginine, similarly enhanced acetylcholine and flow-induced maximal dilations and abolished the differences between high- and low-salt arterioles. These data show that arteriolar arginase expression is increased and that endothelium-dependent vasodilation is decreased in high-salt Dahl-S rats. Acute pretreatment with an arginase inhibitor or with L-arginine restores endothelium-dependent vasodilation and abolishes the differences between high- and low-salt groups. These results suggest that enhanced vascular arginase activity contributes to endothelial dysfunction in Dahl-S rats with salt-induced hypertension and identifies arginase as a potential therapeutic target to prevent endothelial dysfunction.
 ...
PMID:Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension. 1559 Nov 55

L-arginine is a basic endogenous amino acid. Its significant metabolic role as the product of ammonia detoxification, the urea cycle metabolite, the precursor of proteins, ornithine, urea and creatinine, and the amino acid involved in the formation of active enzyme centers was very well established. The current interest in this amino acid refers mainly to its close relation with an important signal molecule nitric oxide (NO). Literature review demonstrates that L-arginine, the only substrate of the NO production, affects cardiovascular system (blood vessels and heart). The majority of experimental and clinical studies clearly show a beneficial effect of L-arginine on endothelium in conditions associated with its hypofunction and thus with reduced NO synthesis. Some clinical studies involving healthy volunteers or patients suffering from hypertension and diabetes indicate that it may also regulate vascular hemostasis. Moreover, experiments performed on animals and in vitro data also suggest that L-arginine may have a complex antiaggregatory, anticoagulatory and profibrinolytic effect. Therefore, a novel therapeutic potential of L-arginine should be taken into consideration.
 ...
PMID:L-arginine and cardiovascular system. 1584 73

Estrogen (E2) acts in the brain to decrease blood pressure (BP) responses to psychological stress. A likely site for the effects of E2 is the hypothalamic paraventricular nucleus (PVN), an important regulator of autonomic functions. We studied the effects of E2 in the PVN on BP and heart rate (HR) responses to l-glutamate injections into the PVN of male urethane-anesthetized rats. Microinjections of l-glutamate (50 nmol) into the PVN increased BP by 14+/-2.5 mm Hg and HR by 30+/-5.6 bpm. Microinjections of E2 (0.1, 1, and 10 pmol) into the PVN 30 minutes before l-glutamate dose-dependently attenuated the pressor response by 25%, 34%, and 59%, respectively, but did not affect HR. We determined that E2 receptor (ER) beta mediates the effect of E2, because activation of ERbeta with diarylpropionitrile (50 pmol) attenuated the response by 57%, whereas activation of ERalpha with propyl-pyrazole-triol (20 pmol) had no effect. Furthermore, inhibition of ERbeta with R,R-tetrahydrochrysene (50 pmol) blocked the effect of E2, but inhibition of ERalpha with methyl-piperidino-pyrazole (1 nmol) did not. Finally, we found that the effect of E2 is mediated by NO, because the NO synthase (NOS) inhibitor, N(G)-nitro-l-arginine methyl ester (2 nmol), the neuronal NOS inhibitor, 7-nitroindazole sodium salt (0.1 pmol), and the endothelial NOS inhibitor, N5-(1-iminoethyl)-l-ornithine (200 pmol) blocked the effect of E2. The effect was partially blocked with the gamma-aminobutyric acid(A) receptor inhibitor bicuculline. Our results demonstrate that E2 in the PVN attenuates the l-glutamate-induced pressor response and that this effect is mediated by ERbeta, NO produced by neuronal NO synthase and eNOS, and partly by gamma-aminobutyric acid.
Hypertension 2006 Dec
PMID:Estrogen in the paraventricular nucleus attenuates L-glutamate-induced increases in mean arterial pressure through estrogen receptor beta and NO. 1707 34

L-citrulline is the natural precursor of L-arginine, substrate for nitric oxide synthase (NOS) in the production of NO. Supplemental administration L-arginine has been shown to be effective in improving NO production and cardiovascular function in cardiovascular diseases associated with endothelial dysfunction, such as hypertension, heart failure, atherosclerosis, diabetic vascular disease and ischemia-reperfusion injury, but the beneficial actions do not endure with chronic therapy. Substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea by arginase makes oral delivery very ineffective. Additionally, all of these disease states as well as supplemental L-arginine enhance arginase expression and activity, thus reducing the effectiveness of L-arginine therapy. In contrast, L-citrulline is not metabolized in the intestine or liver and does not induce tissue arginase, but rather inhibits its activity. L-citrulline entering the kidney, vascular endothelium and other tissues can be readily converted to L-arginine, thus raising plasma and tissue levels of L-arginine and enhancing NO production. Supplemental L-citrulline has promise as a therapeutic adjunct in disease states associated with L-arginine deficiencies.
 ...
PMID:Therapeutic use of citrulline in cardiovascular disease. 1721 3

Hyperhomocysteinemia has been suggested to induce hypertension due to its role in endothelial dysfunction. However, it remains controversial whether homocysteine and hypertension are truly causally related or merely loosely associated. To test the hypothesis that hyperhomocysteinemia occurs in spontaneously hypertensive rats (SHR) we measured plasma levels of homocysteine in 10 male adult SHR and in 10 normotensive controls using ion exchange chromatography. In addition, plasma concentrations of the 22 most common amino acids were measured to explore the relation of homocysteine with amino acid metabolism. Plasma levels of homocysteine were significantly lower in SHR (4.1+/-0.1 micromol/l) than in controls (7.2+/-0.3 micromol/l) (p<0.00001). The amounts of aminobutyric acid, alanine, citrulline and valine were also decreased, whereas we found increased levels of aspartate, glutamate, glutamine, histidine and ornithine. Thus, contrary to our hypothesis, hypertension in SHR occurs despite low plasma levels of homocysteine. We provide a new hypothesis whereby reduced conversion of arginine to citrulline is related to increased ornithine levels, but decreased bioavailability of nitric oxide, resulting in impaired blood vessel relaxation and hypertension. In conclusion, our findings do not necessarily exclude that homocysteine and hypertension might be pathophysiologically connected, but corroborate the notion that hypertension can arise due to mechanisms independent of high homocysteine levels.
 ...
PMID:Hypertension in spontaneously hypertensive rats occurs despite low plasma levels of homocysteine. 1729 1

1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.
 ...
PMID:Arginase: a critical regulator of nitric oxide synthesis and vascular function. 1764 39

Vascular smooth muscle cell (VSMC) proliferation is pivotal in the progression of hypertension, atherosclerosis, and restenosis. Resveratrol is a grape polyphenol that is implicated as an important contributor to red wine's vascular protective effects. Its antimitogenic action on VSMC is attributed to an array of pleiotropic effects, including modulation of the estrogen receptor (ER). To elucidate the mechanisms underlying resveratrol-mediated ER modulation and its inhibition of VSMC proliferation, we treated VSMC with resveratrol with or without the ER antagonist ICI 182,780 and measured cell proliferation and nitric oxide (NO) production. Resveratrol dose-dependently decreased VSMC DNA synthesis, with a half maximal inhibitory concentration (IC50) of 3.73+/-0.57 microM, and dramatically slowed cell growth, but did not induce VSMC apoptosis. Resveratrol-mediated decrease in proliferation was reversed by cotreatment with ICI 182,780, and resveratrol effectively competed with 17beta-estradiol for binding to the ER, exhibiting an IC50 of 8.92+/-0.14 microM. Resveratrol induced a sustained increase in ER-dependent NO production. Further, resveratrol-mediated decrease in VSMC proliferation was blunted by cotreatment with the general nitric oxide synthase (NOS) inhibitor N5-(1-Iminomethyl)-L-ornithine, dihydrochloride or with the inducible NOS (iNOS)-selective inhibitor S,S'-1,4-phenylene-bis (1,2-ethanediyl)bis-isothiourea, dihydrobromide, but not with the neuronal NOS-selective inhibitor 7-nitroindazole. Though resveratrol did not alter iNOS protein levels, it dose-dependently increased levels of iNOS activity, of the iNOS cofactor tetrahydrobiopterin (BH4), and of guanosine triphosphate cyclohydrolase I protein, the rate-limiting enzyme in BH4 biosynthesis. In addition, all of these effects were abolished by cotreatment with ICI 182,780. Thus, the antimitogenic effects of resveratrol on VSMC may be mediated by an ER-induced increase in iNOS activity.
 ...
PMID:Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production. 1766 20


<< Previous 1 2 3 4 5 Next >>