Effects of native and oxidized low-density lipoproteins on endothelium-dependent and endothelium-independent vasomotion.
Native and oxidized low-density lipoproteins (LDL) were investigated for their direct influence on EDRF-formation, EDRF-activity, and vascular smooth muscle tone. Native (n) LDL, isolated from fresh human plasma, was oxidized by Cu(2+)-incubation. EDRF released from cultured endothelial cells was inactivated by both n-LDL and ox-LDL (1 mg/ml) as detected in a bioassay system. n-LDL reduced the EDRF-mediated vasodilations of the detector segments by 38.5 +/- 5.3%, and ox-LDL by 55.5 +/- 4.6%. The effects of lipoproteins on EDRF-formation were studied on cultured endothelial cells, preincubated with either n-LDL or ox-LDL (1 mg/ml, 1 h) and stimulated for EDRF-release with bradykinin after washout of the lipoproteins. EDRF was assessed by measuring its stimulatory effect on the activity of a purified soluble guanylate cyclase. Preincubation with both n-LDL and ox-LDL did not reduce the bradykinin-induced EDRF-formation. Accordingly, acetylcholine-induced, EDRF-mediated dilations of intact rabbit femoral artery segments were not impaired by luminal exposure to n-LDL or ox-LDL (1 h, 1mg/ml). Effects of n-LDL and ox-LDL on vascular smooth muscle tone were investigated in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and -denuded segments with ox-LDL (80-500 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine (NE), serotonin (5-HT), phenylephrine (PE) or potassium were significantly enhanced. Native LDL (80-1000 micrograms/ml) had no effect on vascular tone, neither in presence nor in absence of contractile agonists. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. In conclusion, neither n-LDL nor ox-LDL acutely impair the formation of EDRF, but do inactivate EDRF after its release from endothelial cells. n-LDL has no direct influence on vascular smooth muscle tone, but ox-LDL greatly enhances vasoconstrictions to various contractile agonists by direct interaction with vascular smooth muscle. Thus, in regions of lipoprotein-accumulation in the arterial wall, both n-LDL and ox-LDL may favor inappropriate vasoconstrictions.
Galle
J
J
Department of Applied Physiology, University of Freiburg, FRG.
Bassenge
E
E
D000818:Animals; D001011:Aorta; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005263:Femoral Artery; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology
D008077:Lipoproteins, LDL; D010656:Phenylephrine; D009569:Nitric Oxide; D012701:Serotonin; D009638:Norepinephrine