Dexnafenodone is a dual of adrenergic receptor antagonist and serotonin uptake inhibitor potentially for the treatment of major depressive disorder. Drug induced a rapid and marked suppression of REM sleep, and in parallel an increase in chin muscle tone during NREM sleep. Dexnafenodone produced a frequency- and voltage-dependent inhibition of the fast sodium channels similar to that exhibited with imipramine. It 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, dexnafenodone would reduce the concentration of intracellular free Ca2+ available at the contractile apparatus for vascular smooth muscle contraction. Dexnafenodone exerted fewer cardiodepressant effects than imipramine and desipramine in isolated guinea-pig atrial and ventricular muscle fibres less.