P112Calcium channels influence of mifipristone vasorelaxation on vascular smooth muscle cells

Abstract

Introduction: Mifepristone (RU 486) is a compound derived from the estrane progestins and related to steroid hormones. It was the first synthetic steroid of this class employed as abortifacient in the first months of pregnancy. The treatment with this drug reduces high potassium-induced contraction, prevents calcium-induced contraction in depolarized tissue and relaxes the oxytocin and prostaglandin-induced contractions. At the vascular level, mifepristone induces direct relaxation in rats and human arteries. This effect is endothelium- and NO-independent, suggesting that the vascular smooth muscle is the target of its action. Moreover, this effect induced by mifepristone may involve inactivation or activation of several calcium channels. In this sense, the aim of the present study is to analyse the involvement of calcium and potassium channels in the relaxation induced by RU 486 on vascular smooth muscle cells (VSMC). Methods: Planar Cell Surface Area (PCSA) technique was used to analyze the effect of RU 486 on the VSMC contractility. The A7r5 cell line were contracted using norepinephrine (1μM) or serotonin (1μM) and the effect induced by RU 486 (0.1–100 μM) was analyzed. Moreover, the whole cell configuration of Patch Clamp technique was also used to measure the activity of L-type Ca2+ channels (LTCC) and K+ channels in A7r5 cells. The effect of different concentrations of RU 486 (0.1-100μM) on basal and stimulated (-)-Bay K8644 (BAY) activity of LTCC and on K+ currents was analyzed. Results: Regarding the PCSA technique, mifepristone induce relaxation of the VSMC, for all the contractile agents used. Concerning the RU 486 effects in the calcium currents, our results revealed a rapid concentration-dependent inhibitory effect on basal and BAY-stimulated calcium current, which indicates that this drug have the ability to block LTCC. However, RU 486 did not have any influence on the potassium current that is mainly constituted by voltage-sensitive and large-conductance Ca2+-activated potassium channels. Conclusions: These results suggest that mifepristone induces relaxation on the vascular smooth muscle cells due to the inhibition of the calcium channels, and the K+ channels are not involved in this effect.