6533b7dafe1ef96bd126ec67

RESEARCH PRODUCT

Relaxant and antiadrenergic effects of ranolazine in human saphenous vein.

subject

description

Abstract 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, α1 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, NG-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 (2–4 Hz) and phenylephrine (10−9–10−5 M) that were prevented by tetraethylammonium (10−3 M) and charybdotoxin (10−7 M). Ranolazine significantly decreased α1 adrenergic receptor and increased large conductance Ca2+-activated K+ channel protein expression in the saphenous vein. CONCLUSIONS Ranolazine diminishes the adrenergic vasoconstriction, acting as α1 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.