Effects of Ranolazine on Vascular Adrenergic Receptors in Rabbit Aorta

Background: Different mechanisms of action have been proposed for Ranolazine (Rn), mainly the inhibition of the late sodium current and antagonism of -adrenergic receptors.In the present study, we evaluated the possible involvement of other adrenergic receptors, specifically , , and , as mediators of the vascular effects of Rn.Methods: Segments of rabbit aorta were mounted in an organ bath.Electrical field stimulation (EFS; 2, 4, and 8 Hz) induced frequency-dependent contractions that were abolished by tetrodotoxin, prazosin, or guanethidine (10 M), confirming the neural origin of the vascular responses.The effects of Rn on vascular responses to adrenergic stimulation were evaluated by incubating the preparations with increasing concentrations of the drug (10-10 M) for 20 minutes prior to neural stimulation (4 Hz).The involvement of -, -, -, or -adrenergic receptors was assessed using specific antagonists (10 M): prazosin (), yohimbine (), butaxamine (), and SR59230A ().Subsequently, the sequence of electrical field stimulations was performed in the presence of Rn.Expression levels of -, -, -, and -adrenergic receptors were determined by Western blot analysis.Results: Rn decreases the contractile effect induced by adrenergic nerve stimulation in the rabbit aorta.In the presence of prazosin or yohimbine, the vasoconstrictor response was significantly reduced.However, incubation with butaxamine or SR59230A significantly increased the contractile response to adrenergic nerve stimulation.The protein expression of 1 and 2 receptors significantly decreased compared to the control when incubated with Rn.In contrast, the expression of 2 and 3 receptors increased only at 10 M, a concentration lower than that reached with therapeutic doses of Rn.Conclusion: Rn inhibits the vasoconstrictor response to adrenergic nerve stimulation through an antagonistic effect on 1 and 2 receptors and enhancing the vasodilatory responses mediated by 2 and 3 adrenergic receptors.