Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs

Mads Damkjaer, Gorm Nielsen, Silke Bodendiek, Mette Staehr, Jan Bert Gramsbergen, Cor De Wit, Boye L. Jensen, Ulf Simonsen, Peter Bie, Heike Wulff, Ralf Köhler

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

BACKGROUND AND PURPOSE In rodents, the endothelial KCa channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium-derived hyperpolarizing factor (EDHF) vasodilator responses. However, it is not known to what extent these channels are involved in blood pressure regulation in large mammals, which would also allow us to address safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect of the KCa3.1/KCa2.3 activator SKA-31 on blood pressure and heart rate in dogs. EXPERIMENTAL APPROACH Canine endothelial KCa3.1/KCa2.3 functions were studied by patch-clamp electrophysiology and wire myography in mesenteric arteries. Systemic cardiovascular actions of acute SKA-31 administration were monitored in conscious, unstressed beagle dogs. KEY RESULTS Mesenteric endothelial cells expressed functional KCa3.1 and KCa2.3 channels that were strongly activated by SKA-31. SKA-31 hyperpolarized the endothelial membrane and doubled endothelial hyperpolarization-dependent vasodilator responses in mesenteric arteries. SKA-31 (2 mg·kg -1, i.v.) rapidly decreased the MAP by 28 ± 6 mmHg; this response was transient (8 ± 1 s), and the initial drop was followed by a fast and pronounced increase in HR (+109 ± 7 beats min -1) reflecting baroreceptor activation. SKA-31 significantly augmented similar transient depressor responses elicited by ACh (20 ng·kg -1) and doubled the magnitude of the response over time. CONCLUSIONS AND IMPLICATIONS Activation of endothelial KCa3.1 and KCa2.3 lowers arterial blood pressure in dogs by an immediate electrical vasodilator mechanism. The results support the concept that pharmacological activation of these channels may represent a potential unique endothelium-specific antihypertensive therapy.

Original languageEnglish (US)
Pages (from-to)223-234
Number of pages12
JournalBritish Journal of Pharmacology
Volume165
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • blood pressure
  • endothelium-derived hyperpolarizing factor
  • hypertension
  • intermediate-conductance calcium-activated potassium channel
  • SKA-31
  • small-conductance calcium-activated potassium channel

ASJC Scopus subject areas

  • Pharmacology

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    Damkjaer, M., Nielsen, G., Bodendiek, S., Staehr, M., Gramsbergen, J. B., De Wit, C., Jensen, B. L., Simonsen, U., Bie, P., Wulff, H., & Köhler, R. (2012). Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs. British Journal of Pharmacology, 165(1), 223-234. https://doi.org/10.1111/j.1476-5381.2011.01546.x