antihypertensive treatment differentially affects vascular sphingolipid biology in spontaneously hypertensive rats抗高血压治疗不同的影响在自发性高血压大鼠血管鞘脂类生物.pdf

Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats ´ 1 2 2 2 3 Leon J. A. Spijkers , Ben J. A. Janssen , Jelly Nelissen , Merlijn J. P. M. T. Meens , Dayanjan Wijesinghe , 3 2 1 1 Charles E. Chalfant , Jo G. R. De Mey , Astrid E. Alewijnse , Stephan L. M. Peters * 1 Department of Pharmacology Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands, 2 Department of Pharmacology, Maastricht University, Maastricht, The Netherlands, 3 Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America Abstract Background: We have previously shown that essential hypertension in humans and spontaneously hypertensive rats (SHR), is associated with increased levels of ceramide and marked alterations in sphingolipid biology. Pharmacological elevation of ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A2, cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A2. This phenomenon is almost absent in vessels from normotensive Wistar Kyoto (WKY) rats. Here we investigated whether lowering of blood pressure can reverse elevated ceramide levels and reduce ceramide-mediated contractions in SHR. Methods and Findings: For this purpose SHR were treated for 4 weeks with the angiotensin II type 1 receptor antagonist losartan or the vasodilator hydralazine. Both drugs decreased blood pressure equally (SBP untreated SHR: 19167 mmHg, losartan: 12565 mmHg and hydralazine: 113614 mmHg). The blood