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.

• Authors: Josephine Radtke, Kjestine Schmidt, Heike Wulff, Ralf Köhler, Cor de Wit
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 2 Pg. 293-303 (Sep 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23734697 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Benzothiazoles
• Connexins
• Intermediate-Conductance Calcium-Activated Potassium Channels
• Kcnn4 protein, mouse
• Pyrazoles
• TRAM 34
• connexin 40
• naphtho(1,2-d)thiazol-2-ylamine

Topics

• Animals
• Benzothiazoles (administration & dosage, pharmacology)
• Blood Pressure (drug effects)
• Connexins (genetics)
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects)
• Endothelium, Vascular (drug effects)
• Gap Junctions (drug effects, metabolism)
• Genotype
• Heart Rate (drug effects)
• Hypertension (drug therapy, physiopathology)
• Intermediate-Conductance Calcium-Activated Potassium Channels (drug effects, metabolism)
• Mice
• Mice, Knockout
• Microcirculation (drug effects)
• Pyrazoles (pharmacology)
• Telemetry
• Vasodilation (drug effects)