Abstract
BackgroundWe 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 FindingsFor 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 A2. The latter finding may explain the effect of losartan treatment on sphingomyelinase-induced vascular contraction.ConclusionIn 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.
Highlights
Sphingolipids are a class of bioactive lipids with important roles in cell signaling as they control cell growth, migration and differentiation [1,2,3,4]
In summary, this study corroborates the importance of sphingolipid biology in blood pressure control and shows that blood pressure lowering reduces vascular ceramide levels in spontaneously hypertensive rats (SHR) and that losartan treatment, but not blood pressure lowering per se, reduces ceramide-mediated arterial contractions
The pathophysiological relevance of this finding was demonstrated by the observation that pharmacological elevation of ceramide in isolated carotid arteries of SHR but not Wistar Kyoto (WKY), leads to endothelium-dependent arterial contractions by thromboxane A2 (TXA2) and increases blood pressure in SHR in vivo [10]
Summary
Sphingolipids are a class of bioactive lipids with important roles in cell signaling as they control cell growth, migration and differentiation [1,2,3,4]. We have previously shown that sphingolipids are involved in the pathophysiology of hypertension in vivo [10] This latter study showed that vascular and plasma levels of the bioactive sphingolipid ceramide were significantly higher in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto (WKY) rats. The pathophysiological relevance of this finding was demonstrated by the observation that pharmacological elevation of ceramide in isolated carotid arteries of SHR but not WKY, leads to endothelium-dependent arterial contractions by thromboxane A2 (TXA2) and increases blood pressure in SHR in vivo [10]. 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.
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