MECHANISMS UNDERLYING THE VASORELAXING EFFECTS OF CORM-3, A WATER-SOLUBLE CARBON MONOXIDE-RELEASING MOLECULE

The mechanism responsible for vasomotion the oscillation of vascular tone – is still incompletely understood. In particular the role of EDHF is uncertain. In this study we have tested the effect of inhibition of EDHF for vasomotion. We have further been interested in the role of the endoplasmic Ca-ATPase for the impact of EDHF on vasomotion. Isolated rat mesenteric arteries were studied in vivo (in anaesthetized rats) and in vitro (under isometric conditions). Under both conditions vasomotion is seen with a frequency of 10-15 min-1 during agonist stimulation. Application of TRAM and apamin had no effect on vasomotion frequency or amplitude. Inhibition of the endoplasmic Ca-ATPase using cyclopiazonic acid (CPA) induced a low frequency (about 1 min-1) high amplitude oscillation in vitro. This oscillation was associated with oscillations of [Ca2+]I , which was antiphase between endothelial and smooth muscle cells SMC) and in-phase oscillations of membrane-potential in endothelial and SMCs. This oscillation of tone reverted to the high frequency low amplitude oscillation seen under control conditions when IKCa and SKCa were inhibited. We conclude that CPA induced inhibition of the Ca2+ buffer capacity of the endoplasmic reticulum enhances the EDHF through an increase of the amplitude of [Ca2+]I oscillations in the endothelium. The data suggest that EDHF is strongly dependent on the function of endothelial cell endoplasmic reticulum.