title: Antihypertensive treatment differentially affects vascular sphingolipid biology in spontaneously hypertensive rats.
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 A(2), cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A(2). 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.
  
  
  RESULTS
  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: 191±7 mmHg, losartan: 125±5 mmHg and hydralazine: 113±14 mmHg). 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 both drugs lowered cyclooxygenase-1 expression, only losartan and not hydralazine, reduced the endothelial expression of calcium-independent phospholipase A(2). The latter finding may explain the effect of losartan treatment on sphingomyelinase-induced vascular contraction.
  
  
  CONCLUSIONS
  In summary, this study corroborates the importance of sphingolipid biology in blood pressure control and specifically shows that blood pressure lowering reduces vascular ceramide levels in SHR and that losartan treatment, but not blood pressure lowering per se, reduces ceramide-mediated arterial contractions.
authors.affiliation: Department of Pharmacology & Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Léon J A
authors.initials: LJ
authors.lastname: Spijkers
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Jelly
authors.initials: J
authors.lastname: Nelissen
authors.forename: Merlijn J P M T
authors.initials: MJ
authors.lastname: Meens
authors.forename: Dayanjan
authors.initials: D
authors.lastname: Wijesinghe
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Alewijnse
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002518:Ceramides / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D054522:Group VI Phospholipases A2 / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D002518:Ceramides; D013107:Sphingolipids; D006830:Hydralazine; D054522:Group VI Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase; D019808:Losartan