NO-1886, a lipoprotein lipase activator, attenuates vascular smooth muscle contraction in rat aorta

The chemical compound [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886) is a lipoprotein lipase activator having beneficial effects on both diabetes control and the cardiovascular system. Preventing accumulation of lipids in the cell wall, in addition to improving insulin actions on vasculature, may indirectly contribute to the reducing effect of NO-1886 on vascular resistance. However, the direct effect of NO-1886 on vascular resistance, i.e., whether NO-1886 directly modulates the function of vascular endothelium and/or smooth muscle cells has not been investigated. In this study we therefore investigated the direct effect of NO-1886 on vascular contractility using rat aortic rings and cultured smooth muscle cell-line A10. The results show that administration of NO-1886 attenuated aortic contraction induced by phenylephrine and/or a high K+ environment, in both the presence and absence of aortic endothelium. 1-(5-Chloronaphthalene-1-sulfonyl)homopiperazine hydrochloride (ML-9), a myosin light chain kinase (MLCK) inhibitor, blocked this inhibitory effect of NO-1886, whereas inhibitors of other signaling molecules such as calmodulin, protein kinase C and Rho-kinase had no effect. The vasorelaxant effect of NO-1886 was blocked in the absence of extracellular Ca2+, or in the presence of the Ca2+ channel inhibitor, verapamil. NO-1886 attenuated smooth muscle contraction induced by the cumulative addition of CaCl2. In A10 cells, NO-1886 inhibited the membrane depolarization-induced initial peak of [Ca2+]i in the presence of extracellular Ca2+. This inhibition did not occur in the absence of extracellular Ca2+. Taken together these results demonstrate that NO-1886 attenuates smooth muscle contraction and causes vasorelaxation by an extracellular Ca2+- and MLCK-dependent mechanism.