Relaxant And Antiadrenergic Effects Of Ranolazine In Human Saphenous Vein

OBJECTIVES: Ranolazine improves vascular function in animal models. We evaluate the effects of ranolazine on vascular function and adrenergic response in human saphenous vein.METHODS: Rings from 53 patients undergoing coronary artery bypass grafting were mounted in organ baths. Concentration-response curves to ranolazine were constructed in rings precontracted with phenylephrine, endothelin-1, vasopressin, KCl and the thromboxane A2 analogue U-46619. In rings precontracted with phenylephrine, relaxation to ranolazine was tested in the absence and presence of endothelial factors inhibitors, K+ channel blockers and verapamil. The effects of ranolazine on frequency-response and concentration-response curves to phenylephrine were performed in the absence and presence of endothelial factors inhibitors and K+ channel blockers. Endothelial nitric oxide synthase, alpha(1) adrenergic receptor and large conductance Ca2+-activated K+ channel protein expressions were measured by Western blotting.RESULTS: Ranolazine (10(-9)-10(-4) M) produced a concentration-dependent relaxation only in rings precontracted with phenylephrine that was reduced by endothelial denudation, N-G-nitro-l-arginine methyl ester (10(-4) M), charybdotoxin (10(-7) M) and verapamil (10(-6) M). Ranolazine diminished adrenergic contractions induced by electrical field stimulation (2-4Hz) and phenylephrine (10(-9)-10(-5) M) that were prevented by tetraethylammonium (10(-3) M) and charybdotoxin (10(-7) M). Ranolazine significantly decreased alpha(1) adrenergic receptor and increased large conductance Ca2+-activated K+ channel protein expression in the saphenous vein.CONCLUSIONS: Ranolazine diminishes the adrenergic vasoconstriction, acting as alpha(1) antagonist, and by increasing large conductance Ca2+-activated K+ channel involvement. The relaxant effects of ranolazine are partially mediated by endothelial nitric oxide, large conductance Ca2+-activated K+ channels and the blockade of voltage-dependent Ca2+ channels.