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

Hermann, Matthias ; Ruschitzka, Frank ; Camici, Giovanni ; Shaw, Sidney ; Luscher, Thomas F.

In: American Journal of Hypertension, 2003, vol. 16, no. S1, p. 24A-24A

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    Titel
    • OR-53: HMG-CoA reductase inhibitor improves endothelial dysfunction in mineralocorticoid hypertension by inhibition of RhoA
    Autor
    • Hermann, Matthias. Cardiovascular Research, University Zurich-Irchel, Zurich, Switzerland; Cardiovascular Center, University Hospital, Zurich, Switzerland; Department of Clinical Research, Inselspital Bern, Bern, Switzerland
    • Ruschitzka, Frank. Cardiovascular Research, University Zurich-Irchel, Zurich, Switzerland; Cardiovascular Center, University Hospital, Zurich, Switzerland; Department of Clinical Research, Inselspital Bern, Bern, Switzerland
    • Camici, Giovanni. Cardiovascular Research, University Zurich-Irchel, Zurich, Switzerland; Cardiovascular Center, University Hospital, Zurich, Switzerland; Department of Clinical Research, Inselspital Bern, Bern, Switzerland
    • Shaw, Sidney. Cardiovascular Research, University Zurich-Irchel, Zurich, Switzerland; Cardiovascular Center, University Hospital, Zurich, Switzerland; Department of Clinical Research, Inselspital Bern, Bern, Switzerland
    • Luscher, Thomas F.. Cardiovascular Research, University Zurich-Irchel, Zurich, Switzerland; Cardiovascular Center, University Hospital, Zurich, Switzerland; Department of Clinical Research, Inselspital Bern, Bern, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • American Journal of Hypertension, 2003, vol. 16, no. S1, p. 24A-24A. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:304354
    Summary
    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 system