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Abstract:The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N w -nitro-L-arginine methyl esther (L-NAME; 20 mg ⁄ kg, i.v.). In phenylephrine (10 lM), pre-contracted mesenteric artery rings, milonine (10 )10 M to 3 · 10 )4 M) caused a concentration-dependent relaxation (EC 50 = 1.1 · 10 )6 M, E max = 100 € 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC 50 = 1.6 · 10 )5, p < 0.001), or after L-NAME 100 lM (EC 50 = 6.2 · 10 , p < 0.001). Milonine also reduced CaCl 2 -induced contraction in Ca 2+ -free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide-cGMP pathway and opening of K + channels.