Dataset Information

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

ABSTRACT:

Background and purpose

The calcium-activated potassium channel KCa3.1 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 (Cx40(fl/fl):Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ?38 mV) in Cx40(fl/fl):Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40(-/-)) and controls (Cx40(fl/fl)), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40(fl/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.

SUBMITTER: Radtke J

PROVIDER: S-EPMC3834754 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Radtke Josephine J Schmidt Kjestine K Wulff Heike H Köhler Ralf R de Wit Cor C

British journal of pharmacology 20130901 2

<h4>Background and purpose</h4>The calcium-activated potassium channel KCa3.1 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 i ...[more]

PMID: 23734697

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Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

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