Background-Several clinical studies have demonstrated a close association between plasma HDL cholesterol levels and endothelium-dependent vasodilation in peripheral arteries. In isolated arteries, HDL has been shown to mediate vasodilation via NO release. In vivo, administration of reconstituted HDL restored abnormal endothelial function of the brachial artery in hypercholesterolemic patients. However, no data are currently available on the effect of HDL on myocardial perfusion. Methods and

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... lts-In this study, administration of human HDL enhanced incorporation of the perfusion tracer 99m Tc-methoxyisobutylisonitrile ( 99m Tc-MIBI) into the murine heart in vivo by Ϸ18%. This increase was completely abolished in mice deficient for endothelial NO synthase. Because we have recently identified sphingosine 1-phosphate (S1P) as an important vasoactive component contained in HDL, we measured myocardial perfusion after administration of S1P in vivo. We observed an Ϸ25% decrease in myocardial MIBI uptake, which was abolished in mice deficient for the S1P receptor S1P 3 . In S1P 3 Ϫ/Ϫ mice, the stimulatory effect of HDL on myocardial perfusion was preserved. Conclusions-HDL increased myocardial perfusion under basal conditions in vivo via NO-dependent mechanisms, whereas S1P inhibited myocardial perfusion through the S1P 3 receptor. Thus, HDL may reduce coronary risk via direct NO-mediated vasodilatory effects on the coronary circulation. (Circulation. 2004;110:3355-3359.)