Nebivolol prevents coronary artery spasm by upregulating voltage-gated potassium channels via protein kinase A

Nebivolol (Neb) relaxes coronary arteries and increases coronary artery blood flow, but the underlying mechanisms need further elucidation. The vascular tension of rat coronary artery (RCA) was recorded with a wire myograph. Transmembrane K⁺ currents through voltage-dependent K⁺ (Kv) channels were measured with a patch clamp. Kv1.2 expressions were evaluated with immunofluorescent staining and Western blot. Neb (0.1-30 μM) evoked marked relaxation in RCAs pre-contracted with KCl or U46619. Denudation and L-NAME pretreatment weakened the relaxation by less than 20 %. Neb pretreatment depressed contractile responses of RCAs to various vasoconstrictors including 60 mM KCl, 0.3 μM U46619 and 0.1 μM Bay K8644. In the arterial smooth muscle cell (ASMC) of RCA, Neb reduced 60 mM KCl-induced elevation of intracellular Ca²⁺ ([Ca²⁺]_in)-sensitive fluorescent intensity and increased Kv currents. Incubation of RCAs with Neb increased Kv1.2 expressions in RCA ASMCs. Inhibitor study showed that Kv channel inhibitor 4-aminopyridine (4-AP, 1 mM) and protein kinase A (PKA) inhibitor H-89 (1 μM) attenuated Neb-induced RCA relaxation and Kv current increment in RCA ASMCs, while p38 MAPK inhibitor SB239063 (1 μM) had no effect. In summary, the present study demonstrated that Neb relaxed RCAs through PKA-mediated upregulation of Kv channels in RCA ASMCs.