Abstract
Ceramide, sphingosine and sphingosine‐1‐phosphate (S1P) are signaling molecules generated from membrane phospholipids by a concerted action of several enzymes. These sphingomyelin metabolites (SM) have growth regulating properties; while S1P is implicated in growth stimulation, ceramide and sphingosine (the precursors of S1P) induce apoptosis. In addition, SM have vasoactive properties. For instance S1P, synthesized by sphingosine kinase, can increase NO production in endothelial cells and thereby induce vasodilation. Hypertension is a disease state characterized by endothelial dysfunction (decreased NO bioavailability) and vascular growth (remodeling). Therefore we investigated whether hypertension alters the vasoactive properties of locally produced SM. Inhibition of sphingosine kinase by means of dimethylsphingosine (DMS, 10 μM) induced a biphasic and transient contraction in isolated rat carotid arteries from spontaneous hypertensive but not normotensive animals. This contraction was endothelium and eicosanoid‐dependent since removal of the endothelium and inhibition of cyclooxygenase completely prevented DMS‐induced constriction. Alterations in sphingolipid metabolism may thus contribute to a disturbed regulation of vascular tone during hypertension.This research was performed within the framework of project T2‐108 of the Dutch Top Institute Pharma.
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