The influence of native and oxidized chylomicron-remnant-like particles (CMR-LPs) on endothelium-dependent relaxation in pig coronary arteries was studied. Artificial lipid particles of a size and lipid composition resembling chylomicron remnants and containing pig apolipoprotein E were used to investigate the effects of chylomicron remnants on the relaxation of isolated segments of pig coronary arteries in response to three endothelium dilators: 5-hydroxytryptamine (5-HT), bradykinin and the calcium ionophore A23187. CMR-LPs caused significant inhibition of the maximum relaxation response of the vessels to 5-HT, but not that to bradykinin or A23187 (P<0.05). In contrast, CMR-LPs that had been oxidized by incubation with 10μM CuSO4 (oxidized CMR-LPs) were found to significantly reduce maximal relaxation to bradykinin by 13% (P<0.05) and to reduce the sensitivity of the tissue to A23187 by 1.7-fold (P<0.05). In experiments in which either the L-arginine/nitric oxide (NO) pathway or the endothelium-derived hyperpolarizing factor (EDHF) pathway was selectively inhibited, leaving the other intact, the inhibitory effect of oxidized CMR-LPs was observed only in vessels in which the L-arginine/NO-mediated pathway was operative. Furthermore, the oxidized particles had no inhibitory effect on the relaxation of the vessel segments to the non-endothelium-dependent agonists S-nitro-N-acetylpenicillamine, 5'-(N-ethylcarboxamido)adenosine or pinacidil. These results demonstrate that CMR-LPs inhibit vascular relaxation in pig coronary arteries by an endothelium-dependent mechanism involving the L-arginine/NO pathway, but not the EDHF pathway, and provide evidence in support of a role for chylomicron remnants in the endothelial dysfunction associated with hypercholesterolaemia and atherogenesis.

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1

Present address: Pharmagene plc, 2 Orchard Road, Royston, Herts. SG8 5HD, U.K.