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Activation of KCa3.1 by SKA-31 induces arteriolar dilatation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice

  • Author(s): Radtke, J
  • Schmidt, K
  • Wulff, H
  • Köhler, R
  • De Wit, C
  • et al.

Published Web Location

https://doi.org/10.1111/bph.12267
Abstract

Background and Purpose The calcium-activated potassium channel K Ca3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations 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 KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ∼40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40fl/fl:Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40 -/-) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40fl/fl:Tie2-Cre as well as in hypertensive Cx40-/- animals, i.p. injections of SKA-31 (30 and 100 mg·kg-1) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg-1 SKA-31 was associated with a decrease in heart rate. Conclusions and Implications We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension. © 2013 The British Pharmacological Society.

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