1 Kardiovaskulær og Renal Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU2 unknown3 Forskningsgruppen for Bæredygtighed, innovation og politik4 Kardiovaskulær og Renal Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU
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