Ranolazine attenuates mouse detrusor contractility: Evidence for the involvement of calcium-related mechanisms

Ranolazine (RNZ) is a multifaceted ion channel modulator approved for the treatment of angina. Although various pleiotropic effects on the cardiovascular system have been demonstrated, its efficacy in the urinary system remains not fully understood. Here, we aimed to investigate the effect of RNZ on mouse detrusor smooth muscle (DSM) contractility and the mechanism(s) of its action by using isolated tissue bath technique. RNZ significantly decreased carbachol (CCh)-, KCl- and electrical field stimulation-induced contractility and induced relaxation in DSM concentration-dependently. Furthermore, RNZ-induced relaxation of KCl-precontracted DSM strips was not altered in the presence of 4-aminopyridine, BaCl₂, glibenclamide, TEA, propranolol, L-NAME or methylene blue, indicating that K⁺ channels, nitric oxide/cGMP pathway or β-adrenoreceptors are not involved in the relaxant effect of RNZ. Also, RNZ significantly inhibited the contractile response induced by CaCl₂, CCh, and Bay K8644 under Ca⁺⁺-free conditions. Regarding the molecular docking and cytosolic Ca⁺⁺ mobilization assays, RNZ showed affinity for the antagonist binding site of L-type Ca⁺⁺ channels and significantly decreased cytosolic Ca⁺⁺ level in A7r5 cells. These findings suggest the inhibition of Ca⁺⁺ influx and release may contribute to RNZ-induced DSM relaxation. Hence, our results provide strong evidence that RNZ has a notable relaxant effect on mouse DSM by inhibiting Ca⁺⁺ influx and release of Ca⁺⁺ from intracellular stores and it has the potential to be a therapeutic candidate for LUTS.