Effects of (S)-nafenodone on 45Ca2+ fluxes and contractions in rat isolated vascular smooth muscle.
The effects of (S)-nafenodone, a new antidepressant, were studied on contraction and 45Ca2+ 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 Ca(2+)-free high-K+ solution IC50 = 2.5 +/- 0.9 x 10(-6) M) and the phasic contractions induced by noradrenaline in Ca(2+)-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 45Ca2+ uptake stimulated by high KCl or noradrenaline without altering 45Ca2+ uptake in resting strips and decreased the net 45Ca2+ content in aortic strips non-stimulated as well as stimulated by noradrenaline. In conclusions, (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.
Pérez-Vizcaíno
F
F
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Carrón
R
R
Delpón
E
E
Duarte
J
J
Tamargo
J
J
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D011189:Potassium Chloride / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D000928:Antidepressive Agents; D002121:Calcium Channel Blockers; D009281:Naphthalenes; C071003:nafenodone; D011189:Potassium Chloride; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D009638:Norepinephrine