title: Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Damkjaer
authors.forename: Gorm
authors.initials: G
authors.lastname: Nielsen
authors.forename: Silke
authors.initials: S
authors.lastname: Bodendiek
authors.forename: Mette
authors.initials: M
authors.lastname: Staehr
authors.forename: Jan-Bert
authors.initials: JB
authors.lastname: Gramsbergen
authors.forename: Cor
authors.initials: C
authors.lastname: de Wit
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.forename: Peter
authors.initials: P
authors.lastname: Bie
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D012333:RNA, Messenger; D014665:Vasodilator Agents; C535212:naphtho(1,2-d)thiazol-2-ylamine