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

Cardiovascular risk is dramatically increased in patients with end-stage renal disease (ESRD). However, even minor dys-functions such as microalbuminuria or a mild increase in serum creatinine (Cr) have a major impact on cardiovascular risk. Increased cardiovascular risk is present in multiple populations, including general populations, patients with moderate risk such as hypertensives, and high-risk patients including patients with heart failure and myocardial necrosis. There are many mechanisms underpinning the increased cardiovascular risk. Regarding atherosclerosis, the kidney can be victim or villain. On the one hand, both kidney disease per se and renal insufficiency can induce vascular damage, thereby increasing cardiovascular risk. Kidney disease without renal insufficiency can cause an increased prevalence in hypertension, dyslipidemia (nephrotic syndrome), sympathetic system hyperactivity, and in renin angiotensin system hyperactivity. A moderate-severe renal insufficiency can induce an increase in many vasculotoxic substances such as ADMA, lipoprotein(a), homocysteine, disturbances in calcium and phosphate metabolism, anemia and left ventricular hypertrophy. A more severe renal insufficiency can induce the ominous malnutrition-inflammation-atherosclerosis (MIA) syndrome. On the other hand, the kidney can be the victim of atherosclerosis. Ischemic nephropathy, caused by atherosclerotic renal artery disease and atheroembolism from abdominal aorta are two examples. Finally, it is important to consider that the kidney, being an organ with a wide vasculature, could be a sophisticated sensor of subclinical cardiovascular damage.
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PMID:[Hypertension, atherosclerosis and kidney]. 1578 9

The present study was designed to explore whether there are any effects on neurogenic responses in penile small arteries during the development of hypertension in a one-kidney, one-clip (1K1C) model, a non-renin-dependent model of renovascular hypertension. Five weeks after surgery, male Sprague-Dawley rats were given vehicle, bendroflumethiazide (7.5 mg/kg/day), or L-arginine (2 g/kg/day) in their drinking water for five weeks. Experiments were performed on penile small artery rings (150-200 microm) mounted on microvascular myographs for electrical field stimulation (EFS), and erectile tissue was processed for immunohistochemistry. Maximal neurogenic contractions were unmodified in penile preparations. Relaxations induced by EFS were reduced in the presence of ADMA. In 1K1C rats, neurogenic vasorelaxation mediated by nitric oxide (NO) was unaltered, while relaxation resistant to NO synthase inhibition was blunted. L-arginine and bendroflumethiazide lowered blood pressure in 1K1C rats, but vasodilation was still blunted in the penile arteries. Immunoreactivity for factor VIII and neuronal NO synthase was unaltered in penile arteries from 1K1C animals. Endothelium-dependent vasorelaxation evoked by acetylcholine was also blunted in preparations from 1K1C rats, while exogenous NO relaxation was unaffected. Plasma concentrations and urinary excretion of ADMA did not differ among the experimental animals. Our findings indicate that the reduced release of a non-NO vasodilatory neurotransmitter accounts for the impaired neurogenic vasodilation of the penile arteries. Although ADMA inhibits penile vasorelaxation, it is unlikely to affect erectile function in 1K1C rats.
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PMID:Blunted non-nitric oxide vasodilatory neurotransmission in penile arteries from renal hypertensive rats. 1657 96

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2alpha), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age+/-SE: 32.2+/-0.9 and 29.2+/-1.2 years, respectively; P=0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8+/-0.1 mg/L; white Europeans: 0.6+/-0.1 mg/L; P=0.22), isoprostane-F2alpha (black Africans: 42.9+/-1.5 pg/mL; white Europeans: 39.2+/-1.5 pg/mL; P=0.23), and leptin (black Africans: 64.1+/-10.2 ng/mL; white Europeans: 47.8+/-9.8 ng/mL; P=0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34+/-0.02 micromol/L and 0.25+/-0.03 micromol/L; P=0.03). There was no difference in the percentage of glyceryltrinitrate dilatation (P=0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2+/-0.3; white Europeans: 6.3+/-0.4; P=0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation (P=0.02). In turn, race was the only independent determinant of ADMA levels (P=0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans.
Hypertension 2007 Apr
PMID:Asymmetric dimethylarginine and reduced nitric oxide bioavailability in young Black African men. 1726 43

Increased levels of sCD40L (soluble CD40 ligand) have been associated with enhanced in vivo platelet activation, and may represent a molecular link between inflammation and a prothrombotic state. The aim of the present study was to analyse the relationship between platelet activation, endothelial dysfunction, low-grade inflammation and sCD40L in patients with hypertension with or without MA (microalbuminuria). A cross-sectional comparison of sCD40L levels was performed in 25 patients with MH (essential hypertension with MA) pair-matched for gender and age with 25 patients with EH (essential hypertension) and 25 HS (healthy subjects with normotension). Circulating levels of CRP (C-reactive protein), a marker of inflammation, sP-selectin (soluble P-selectin), a marker of in vivo platelet activation, and ADMA (asymmetric dimethylarginine) and vWF (von Willebrand factor), markers of endothelial dysfunction, were analysed in each subject. sCD40L levels were increased in patients with MH compared with either patients with EH (P<0.001) or HS (P<0.0001). A highly significant correlation between plasma sCD40L and sP-selectin (P<0.0001), vWF (P<0.001) or CRP levels (P<0.05) was observed in patients with MH. Multivariate regression analysis showed that sP-selectin was the strongest independent predictor of sCD40L levels (P<0.0001) in patients with MH. Patients with hypertension with both vWF and CRP levels above the median had the highest sCD40L levels (P<0.0001). Factorial ANOVA of all of the patients with hypertension confirmed that only patients with MH with low-grade inflammation had elevated levels of sCD40L. In conclusion, sCD40L levels appear to discriminate a subset of patients characterized by MA and low-grade inflammation, suggesting that inhibition of the CD40/CD40L system may represent a potential therapeutic target in subjects with hypertension at a high risk of cardiovascular events.
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PMID:Association of low-grade inflammation and platelet activation in patients with hypertension with microalbuminuria. 1798 17

Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N(G)-nitro-l-arginine methyl ester (l-NAME) or l-arginine. Blood samples for ADMA, SDMA, and l-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or l-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to l-NAME was attenuated and l-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. l-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.
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PMID:Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. 1803 48

The action of oxidatively modified low-density lipoprotein on vascular endothelial cells has been proposed to be a crucial process leading to endothelial dysfunction and atherogenesis. However, the biochemical mechanism for such action is not clear. We have previously shown that arginine uptake and metabolism are major determinants of endothelial function in heart failure and hypertension. In the present study we therefore aimed to assess the effects of oxidized LDL, a major pro-atherogenic molecule, on endothelial l-arginine metabolism and its uptake. Endothelial cells were exposed to oxidized LDL or native LDL for 24h, and the resultant effects on (1) the intracellular content of arginine and its major metabolites including citrulline, N(G)-hydroxy-l-arginine, asymmetric dimethylarginine, symmetric dimethylarginine and ornithine, (2) [3H]-l-arginine uptake and, (3) the pattern of distribution of cationic amino acid transporter 1, the principal l-arginine transporter, by confocal microscopy. Oxidized LDL (100 microg/mL) reduced intracellular arginine and N(G)-hydroxy-l-arginine contents by 56 and 71% (P<0.05), respectively, with a concomitant 205% increase in ADMA (P<0.05). In conjunction, oxidized LDL reduced endothelial uptake of [3H]-arginine by 60%. Furthermore, incubation of endothelial cells with oxLDL led to internalization of cationic amino acid transporter 1. We demonstrate a novel mechanism, reduced l-arginine transport, by which oxidized LDL impairs the ability of the endothelium to generate nitric oxide.
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PMID:Detrimental effect of oxidized LDL on endothelial arginine metabolism and transportation. 1806 40

Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme that metabolizes asymmetrical N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA), which are competitive endogenous inhibitors of NO synthase. However, it remains unknown whether NO itself influences DDAH activity and/or ADMA/MMA contents to regulate NO generation via a biofeedback mechanism. The present study was designed to examine the effects of NO on intracellular ADMA and MMA contents and DDAH gene expression levels and enzymatic activities in cultured rat aortic endothelial cells. The NO donors SNAP and NOR3 did not influence DDAH-1 expression but increased DDAH-2 mRNA and protein levels in concentration-dependent manners. SNAP upregulated DDAH enzymatic activity and reduced the MMA and ADMA contents but did not affect the symmetrical N(G),N'(G)-dimethyl-L-arginine and L-arginine levels, thereby negating a mediatory role for system y(+) in ADMA/MMA downregulation. The cGMP agonists 8-bromo-cGMP and C-type natriuretic peptide also stimulated DDAH-2 gene and protein expression levels and DDAH activity and increased the amount of nitrite/nitrate released into the culture supernatants. SNAP-induced DDAH-2 gene expression and DDAH activity were significantly inhibited by a protein kinase G inhibitor, KT5823, and a soluble guanylate cyclase inhibitor, ODQ, suggesting a mediatory role for cGMP in NO-induced DDAH-2 expression. Suppression of DDAH-2 mRNA using small interfering RNA technology abrogated NO-induced DDAH-2 expression. These data demonstrate that NO acts on endothelial cells to induce DDAH-2 expression via a cGMP-mediated process to reduce ADMA/MMA. Thus, the DDAH-2-ADMA/MMA-endothelial NO synthase regulatory pathway and NO-induced cGMP constitute a positive feedback loop that ultimately serves to maintain NO levels in the endothelial environment.
Hypertension 2008 Nov
PMID:Nitric oxide upregulates dimethylarginine dimethylaminohydrolase-2 via cyclic GMP induction in endothelial cells. 1882 64

Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5micromol.l(-1) may be below those required to inhibit NOS whose substrate, l-arginine, is present in concentrations many fold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold above those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate:inhibitor ratio (l-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of these three processes that regulate the intracellular levels of ADMA and arginine.
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PMID:Cellular ADMA: regulation and action. 1968 80

It is now widely accepted that hypertension and endothelial dysfunction are associated with an insulin-resistant state and thus with the development of T2DM (Type 2 diabetes mellitus). Insulin signalling is impaired in target cells and tissues, indicating that common molecular signals are involved. The free radical NO* regulates cell metabolism, insulin signalling and secretion, vascular tone, neurotransmission and immune system function. NO* synthesis is essential for vasodilation, the maintenance of blood pressure and glucose uptake and, thus, if levels of NO* are decreased, insulin resistance and hypertension will result. Decreased blood levels of insulin, increased AngII (angiotensin II), hyperhomocysteinaemia, increased ADMA (asymmetric omega-NG,NG-dimethylarginine) and low plasma L-arginine are all conditions likely to decrease NO* production and which are associated with diabetes and cardiovascular disease. We suggest in the present article that the widely reported beneficial effects of exercise in the improvement of metabolic and cardiovascular health are mediated by enhancing the flux of muscle- and kidney-derived amino acids to pancreatic and vascular endothelial cells aiding the intracellular production of NO*, therefore resulting in normalization of insulin secretion, vascular tone and insulin sensitivity. Exercise may also have an impact on AngII and ADMA signalling and the production of pro- and anti-inflammatory cytokines in muscle, so reducing the progression and development of vascular disease and diabetes. NO* synthesis will be increased during exercise in the vascular endothelial cells so promoting blood flow. We suggest that exercise may promote improvements in health due to positive metabolic and cytokine-mediated effects.
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PMID:Exercise and possible molecular mechanisms of protection from vascular disease and diabetes: the central role of ROS and nitric oxide. 1992 17

Maternal undernutrition can cause reduced nephron number and glomerular hypertrophy, consequently leading to adult kidney disease. We intended to elucidate whether NO deficiency evolves to kidney disease vulnerability in offspring from mothers with caloric restriction diets and whether maternal L-citrulline (L-Cit) supplementation can prevent this. Using a rat model with 50% caloric restriction, four groups of 3-month-old male offspring were sacrificed to determine their renal outcome: control, caloric restriction (CR), control treated with 0.25% L-citrulline solution during the whole period of pregnancy and lactation (Cit), and CR treated in the same way (CR+Cit group). The CR group had low nephron numbers, increased glomerular diameter, and an increased plasma creatinine level compared with the control group. Maternal L-Cit supplementation prevented these effects. The CR+Cit and Cit groups developed hypertension beginning at 4 and 8weeks of age, respectively. Plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels were increased, but L-arginine/ADMA ratios (AAR) were decreased in the CR group vs the control group. This was prevented by maternal L-Cit supplementation. Renal cortical neuronal NOS-alpha (nNOSalpha) protein abundance was significantly decreased in the Cit and CR+Cit groups. Collectively, reduced nephron number, reduced renal nNOSalpha expression, increased ADMA, and decreased AAR contribute to the developmental programming of adult kidney disease and hypertension. Although maternal L-Cit supplementation prevents caloric restriction-induced low nephron number and renal dysfunction, it also induces hypertension.
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PMID:Effects of maternal L-citrulline supplementation on renal function and blood pressure in offspring exposed to maternal caloric restriction: the impact of nitric oxide pathway. 2037 84


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