Inhibitors of acyl-coenzyme A:lysolecithin acyltransferase activate the production of endothelium-derived vascular relaxing factor

Abstract

Considerable acyl-CoA:lysolecithin acyltransferase (LAT) activity could be demonstrated in homogenates of cultured bovine endothelial cells. This LAT activity was inhibited by thimerosal and p-hydroxymercuribenzoate in a concentration-dependent manner. Preconstricted strips of rabbit aorta were relaxed by acetylcholine or the LAT inhibitors in a concentration-dependent fashion if the endothelium was intact (maximal effect of both LAT inhibitors at 10(-5) M). In rabbit aortic strips thimerosal also induced a concentration-dependent stimulation of the formation of 6-keto-prostaglandin F1 alpha, the major cyclooxygenase metabolite of this tissue. This effect of thimerosal was more pronounced in endothelium-intact than in endothelium-denuded preparations. Inhibition of prostaglandin synthesis with indomethacin (10(-5) M) did not impair the relaxation. Thimerosal and acetylcholine-induced relaxations were abolished when the endothelium was removed or when endothelium-intact preparations were pretreated with nordihydroguaiaretic acid (3 X 10(-5) M), gossypol (5 X 10(-6) M) or dithiothreitol (3 X 10(-4) M). In contrast, mepacrine (3 X 10(-5) M), that abolished the acetylcholine response, had no effect on the thimerosal relaxation. In other experiments bovine endothelial cells were grown to confluence on microcarrier beads and packed into columns. Adding thimerosal (5 X 10(-6) M) or bradykinin (10(-10) to 10(-8) M) to the medium superfusing the columns induced the release of an unstable nonprostanoid factor (or factors) that relaxed endothelium-denuded rabbit femoral artery segments. Bradykinin induced a transient effect whereas there was a strong and long-lasting release of the factor after administration of thimerosal.(ABSTRACT TRUNCATED AT 250 WORDS)