Inhibition of endothelium-dependent vascular relaxation by lysophosphatidylcholine: Impact of lysophosphatidylcholine on mechanisms involving endothelium-derived nitric oxide and endothelium derived hyperpolarizing factor

Hyperlipidemia has been associated with an increase in the incidence of ath erosclerosis. The oxidation of low density lipoprotein (LDL) plays an impor tant role in the initiation and progression of atherosclerosis, one of its effects being the inhibition of endothelium dependent relaxation (EDR). The elevated level of lysophosphatidylcholine (LPC) in oxidatively modified LD L has been shown to be a biochemical factor responsible for the impairment of EDR in vascular ring preparations. Several endothelium-derived modulator s are thought to control vascular responsiveness. The present work examined whether acetylcholine (ACh)-induced EDR in rat aorta (pre-contracted with phenylephrine, PE) involved both endothelium-derived nitric oxide (EDNO) an d endothelium-dependent hyperpolarizing factor (EDHF) and whether LPC inhib ited either of these selectively. Indomethacin (10(-5) M), had no significa nt effect on EDR, indicating that products of cyclooxygenase, including pro stacyclin, are not involved. Treatment with either N-W-nitro-L-arginine met hyl ester (L-NAME, 6.8 mu M) to inhibit the production of EDNO or with elev ated K+ (15 mM), to block the hyperpolarizing effect of EDHF impaired EDR c onsiderably (each of these shifting the inhibitory dose-response relationsh ip to ACh by almost one log unit); in muscles treated with both of these ag ents EDR was completely inhibited. In each of L-NAME- and K-treated muscles , the addition of LPC (20 mu M) further impaired EDR. LPC did not independe ntly raise the tone of resting- or PE-contracted aorta. We conclude that th e inhibition of EDR of rat aorta by LPC involves the actions of both EDNO a nd EDHF.