EFFECTS OF (S)-NAFENODONE ON CA-45(2+) FLUXES AND CONTRACTIONS IN RAT ISOLATED VASCULAR SMOOTH-MUSCLE

The effects of (S)-nafenodone, a new antidepressant, were studied on contraction and Ca-45(2+) fluxes in rat vascular smooth muscle. In isolated rat aorta (S)-nafenodone, 10(-7) - 10(-4) M, inhibited the contractions induced by 80 mM KCl (IC50 = 1.4 +/- 0.4 X 10(-5) M) and 10(-5) M noradrenaline (IC50) = 1.2 +/- 0.2 x 10(-5) M). (S)-Nafenodone relaxed the contractions induced by both high K+ and noradrenaline, this effect being independent of the presence of functional endothelium. It also inhibited the contractions induced by addition of CaCl2 to Ca2+-free high-K+ solution (IC50 = 2.5 +/- 0.9 x 10(-6) M) and the phasic contractions induced by noradrenaline in Ca2+-free medium, but was a very weak relaxant of the contractions induced by phorbol 12-myristate-13-acetate in Ca2+-free medium. In addition, (S)-nafenodone inhibited the spontaneous mechanical activity in portal vein segments (IC50 = 1.4 +/- 0.8 x 10(-6) M). (S)-Nafenodone inhibited the Ca-45(2+) uptake stimulated by high KCl or noradrenaline without altering Ca-45(2+) uptake in resting strips and decreased the net Ca-45(2+) content in aortic strips non-stimulated as well as stimulated by noradrenaline. In conclusion, (S)-nafenodone inhibited voltage- and agonist-stimulated Ca2+ entry in isolated rat aortas. In addition, it decreased Ca2+ content in both resting and noradrenaline-stimulated muscles, suggesting that it may deplete noradrenaline-sensitive intracellular Ca2+ stores. As a consequence, (S)-nafenodone would reduce the concentration of intracellular free Ca2+ available at the contractile apparatus for vascular smooth muscle contraction,