BACKGROUND AND PURPOSE: The calcium-activated potassium channel KCa 3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilations. We here investigated whether pharmacological activation of KCa 3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilations and pressure depressor responses in vivo. EXPERIMENTAL APPROACH: We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. KEY RESULTS: In wild-type mice, the KCa 3.1-activator naphtho[1,2-d]thiazol-2-ylamine (SKA-31) induced pronounced concentration-dependent arteriolar EDH-type dilations amounting to ∼40% of maximal dilation and enhanced acetylcholine effects. These responses were absent in mice devoid of KCa 3.1 channels. In contrast, SKA-31-induced dilations were not attenuated in mice deficient for Cx40 in endothelial cells (Cx40(fl/fl) :Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38mV) in Cx40(fl/fl) :Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40(-/-) ), and controls (Cx40(fl/fl) ), which were reversed by the specific KCa 3.1-blocker TRAM-34. In normotensive wild-type and Cx40(fl/fl) :Tie2-Cre as well as in hypertensive Cx40(-/-) animals, intraperitoneal injection of SKA-31 (30 and 100 mg/kg) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response was associated with a decrease in heart rate at 100 mg/kg SKA-31. CONCLUSIONS AND IMPLICATIONS: We conclude that an endothelial hyperpolarization through pharmacological activation of KCa 3.1 channels induces EDH-type arteriolar dilations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. Since SKA-31 reduces blood pressure in hypertensive Cx40-deficient mice, KCa 3.1 activators may be useful in severe treatment-resistant hypertension.
British Journal of Pharmacology and Toxicology, 2013, Vol 170, Issue 2