P-274: Activated endothelin system in polyglobulia

The role of the endothelin system, the functional counterpart of NO, in the pathophysiology of polyglobulia remains still elusive. Therefore a novel erythropoietin overexpressing mouse was generated, with hematocrit levels of about 80%. Hence, we analyzed vascular contractions to ET-1 and big endothelin-1 (big ET-1), endothelin-1 (ET-1) promoter activity, ET-1 immunochemistry, endothelin-1 (ET-1)-protein tissue levels, ETA/B-receptor mRNA expression in this novel transgenic model of severe polyglobulia. For analysis of ET-1 promotor activity, EPO transgenic mice were mated with homozygous transgenic mice expressing the lacZ gene under control of the human ET-1 promoter and immunochistochemistry for gal blue was performed in lacZ transgenic animals. Notwithstanding markedly increased eNOS expression, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels indicating enhanced bioavailability of NO, ET-1 tissue levels were also augmented in heart, kidney, liver and aorta (2.2±0.3 vs. 0.5±0.1 pg/mg tissue; P<0.01) of transgenic polyglobulic animals. Accordingly, immunohistochemistry demonstrated enhanced expression of ET-1 protein in the vascular wall of polyglobulic animals as compared to controls (p< 0.05), while increase of ET-1 promoter activity was confined to the perivascular tissue (P<0.05). NOS inhibition with L-NAME unmasked increased vascular reactivity to ET-1 and bigET-1 and aortic ETA/B receptor mRNA gene expression was enhanced (p<0.05 vs. controls). Administration of the NOS inhibitor L-NAME led to acute vasoconstriction of peripheral resistance vessels, hypertension and death of transgenic mice within 2 days, while wildtypes did not show increased mortality. Treatment with the ETA antagonist darusentan doubled survival time of transgenic polyglobulic mice after NO synthase inhibition (p<0.01 vs placebo). In conclusion, in this study we provide first evidence that the tissue endothelin system is activated by polyglobulia. Together with a stimulated NO system it contributes to cardiovascular regulation in pathophysiological conditions associated with increased hematocri

OR-53: HMG-CoA reductase inhibitor improves endothelial dysfunction in mineralocorticoid hypertension by inhibition of RhoA

Statins reduce cardiovascular morbidity and mortality. These beneficial effects are not fully explained by their lipid-lowering action. As such, we investigated the impact of a new statin, rosuvastatin, on endothelial function, the key event in early atherogenesis, in an experimental model of normocholesterolemic hypertension. Hypertension was induced in Wistar-Kyoto rats by inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with Glycyrrhizic acid (GA). 11β-HSD2 provides mineralocorticoid receptor specificity for aldosterone by metabolising glucocorticoids to their receptor inactive 11-dehydro derivatives. GA was added to the drinking water (3 g/L) for 21 days. From days 8 to 21 rosuvastatin (20 mg/kg/d) or placebo were added to chow. Endothelium-dependent and -independent relaxation of isolated aortic rings to acetylcholine (ACh, 10-10-10-5 mol/L) and sodium nitroprusside (SNP, 10-10-10-5 mol/L) was measured. In addition, vascular reactivity to endothelin-1 (ET-1; 10-10-10-7 mol/L) was investigated. ETA and ETB receptor mRNA expression was determined by RT-PCR and RhoA activity by a pull-down assay. Systolic blood pressure increased in rats treated with GA (175 vs 153 mmHg in controls; p<0.01). Endothelium-dependent relaxations to acetylcholine were blunted after GA treatment (p≤0.005 vs control), while the responses to SNP remained unchanged. Rosuvastatin normalized NO-mediated endothelium-dependent relaxation in hypertensive animals (p≤0.01 vs placebo), although blood pressure and cholesterol levels were not affected by the statin. Vascular reactivity to ET-1 was increased by GA (p<0.01 vs control), but not affected by rosuvastatin. ETB receptor mRNA decreased in the GA group (p<0.05 vs control) and was upregulated by rosuvastatin (p<0.005; GA+rosuvastatin vs GA), whereas ETA receptor mRNA upregulation in the GA group (p<0.01 vs control) was partially prevented by the statin. In addition, GA increased Rho-GTP binding (p≤0.05 vs control) which was prevented in both groups by rosuvastatin treatment (p≤0.01 control+rosuvastatin vs control and GA+rosuvastatin vs GA). These data for the first time show that HMG-CoA inhibition improves endothelial dysfunction in normocholesterolemic mineralocorticoid hypertension without affecting blood pressure or cholesterol levels by correction of a stimulated endothelin syste

Quenching Effects in the Hadron Spectrum

Lattice QCD has generated a wealth of data in hadronic physics over the last two decades. Until relatively recently, most of this information has been within the "quenched approximation" where virtual quark--anti-quark pairs are neglected. This review presents a descriptive discussion of the effects of removing this approximation in the calculation of hadronic masses.Comment: To appear in "Lattice Hadron Physics", ed. A.C. Kalloniatis, D.B. Leinweber and A.G. William

P-341: Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension

Renal safety of selective COX-2 inhibitors (coxibs) is a matter of ongoing discussion. Therefore, in the present study we examined the effects of two different coxibs, celecoxib and rofecoxib, compared to a traditional NSAID, diclofenac, and placebo in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib) or placebo were added to chow from week 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T-lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. COX-2 protein and mRNA were isolated from renal cortex. Untreated hypertensive animals showed preglomerular and glomerular injury including endothelial activation/proliferation, broadened adventitia, collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops and especially high grade of glomerulosclerosis (p<0.05 vs DR-placebo) and CD8 and ED1 positive cells (p<0.01 vs DR-placebo) which was improved by celecoxib but not by diclofenac and rofecoxib. Proteinuria was observed in hypertensive animals (p<0.0001 vs DR-placebo), normalised by celecoxib (p=0.0015 vs DS-placebo) and increased by rofecoxib (p<0.05 vs DS-placebo). COX-2 protein and mRNA levels were comparable in all groups. Renal function and morphology improves after celecoxib but not after rofecoxib or diclofenac. This head-to-head comparison demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertensio

P-576: Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension

In view of the ongoing controversy of potential differences in cardiovascular safety of selective COX-2 inhibitors (coxibs), we compared the effects of two different coxibs and a traditional NSAID on endothelial dysfunction, a well established surrogate of cardiovascular disease, in salt-induced hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (4% NaCl) for 56 days. From days 35 to 56, diclofenac (6 mg/kg/d; DS-diclofenac), rofecoxib (2 mg/kg/d; DS-rofecoxib), celecoxib (25 mg/kg/d; DS-celecoxib) or placebo (DS-placebo) were added to the chow. Vascular reactivity of isolated aortic rings was assessed by isometric tension recording. Blood pressure increased with high sodium diet in the DS-groups which was more pronounced after diclofenac and rofecoxib treatment (p<0.005 vs DS-placebo), but slightly blunted by celecoxib (p<0.001 vs DS-placebo). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (ACh, 10−10−10−5 mol/L) in untreated hypertensive rats (p<0.0001 vs DR-placebo). Relaxation to ACh improved after celecoxib (p<0.005 vs DS-placebo and DS-rofecoxib), but remained unchanged after rofecoxib and diclofenac treatment. Vasoconstriction after NOS inhibition with Nω-Nitro-L-Arginine Methyl Ester (10-4 mol/L) was blunted in DS rats (p<0.05 vs DR-placebo), normalized by celecoxib, but not affected by rofecoxib or diclofenac. Protein expression of eNOS was decreased in DS rats with a trend for increased eNOS levels in the DS-celecoxib group (97.8±25.6 vs 54.8±2.8 %, p=0.088 vs DS-placebo). Indicators of oxidative stress, 8-isoprostane levels, were elevated in untreated DS rats on 4% NaCl (6.55±0.58 vs 3.65±1.05 ng/ml, p<0.05) and normalized by celecoxib only (4.29±0.58 ng/ml), while SOD protein expression was decreased in DS rats and not affected by any treatment. Plasma levels of prostaglandines did not change during high sodium diet or any treatment. These data show that celecoxib, but not rofecoxib or diclofenac, improves endothelial dysfunction and reduces oxidative stress, thus pointing to differential effects of coxibs in salt-sensitive hypertension. Am J Hypertens (2004) 17, 243A-243A; doi: 10.1016/j.amjhyper.2004.03.65

Excited Baryons in Lattice QCD

We present first results for the masses of positive and negative parity excited baryons calculated in lattice QCD using an O(a^2)-improved gluon action and a fat-link irrelevant clover (FLIC) fermion action in which only the irrelevant operators are constructed with APE-smeared links. The results are in agreement with earlier calculations of N^* resonances using improved actions and exhibit a clear mass splitting between the nucleon and its chiral partner. An correlation matrix analysis reveals two low-lying J^P=(1/2)^- states with a small mass splitting. The study of different Lambda interpolating fields suggests a similar splitting between the lowest two Lambda1/2^- octet states. However, the empirical mass suppression of the Lambda^*(1405) is not evident in these quenched QCD simulations, suggesting a potentially important role for the meson cloud of the Lambda^*(1405) and/or a need for more exotic interpolating fields.Comment: Correlation matrix analysis performed. Increased to 400 configurations. 22 pages, 13 figures, 15 table