Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats 英文参考文献.docVIP

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Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats 英文参考文献.doc

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Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats 英文参考文献

AntihypertensiveTreatmentDifferentiallyAffects VascularSphingolipidBiologyinSpontaneously HypertensiveRats Le′onJ.A.Spijkers1,BenJ.A.Janssen2,JellyNelissen2,MerlijnJ.P.M.T.Meens2,DayanjanWijesinghe3, CharlesE.Chalfant3,JoG.R.DeMey2,AstridE.Alewijnse1,StephanL.M.Peters1* 1Department of Pharmacology Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands, 2Department of Pharmacology, Maastricht University, Maastricht,TheNetherlands,3DepartmentofBiochemistry,VirginiaCommonwealthUniversity,Richmond,Virginia,UnitedStatesofAmerica Abstract Background:Wehavepreviouslyshownthatessentialhypertensioninhumansandspontaneouslyhypertensiverats(SHR), isassociatedwithincreasedlevelsofceramideandmarkedalterationsinsphingolipidbiology.Pharmacologicalelevationof ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A2, cyclooxygenase-1andthromboxanesynthase-dependentreleaseofthromboxaneA2.Thisphenomenonisalmostabsentin vesselsfromnormotensiveWistarKyoto(WKY)rats.Hereweinvestigatedwhetherloweringofbloodpressurecanreverse elevatedceramidelevelsandreduceceramide-mediatedcontractionsinSHR. MethodsandFindings:ForthispurposeSHRweretreatedfor4weekswiththeangiotensinIItype1receptorantagonist losartanorthevasodilatorhydralazine.Bothdrugsdecreasedbloodpressureequally(SBPuntreatedSHR:1916 7mmHg, losartan: 12565mmHg and hydralazine: 113614mmHg). The blood pressure lowering was associated with a 20–25% reduction in vascular ceramide levels and improved endothelial function of isolated carotid arteries in both groups. Interestingly, losartan, but not hydralazine treatment, markedly reduced sphingomyelinase-induced contractions. While bothdrugsloweredcyclooxygenase-1expression,onlylosartanandnothydralazine,reducedtheendothelialexpressionof calcium-independent phospholipase A2. The latter finding may explain the effect of losartan treatment on sphingomyelinase-inducedvascularcontraction. Conclusion: In summary, this study c