title: SKA-31, a novel activator of SK(Ca) and IK(Ca) channels, increases coronary flow in male and female rat hearts.
abstract: OBJECTIVE
  Endothelial SK(Ca) and IK(Ca) channels play an important role in the regulation of vascular function and systemic blood pressure. Based on our previous findings that small molecule activators of SK(Ca) and IK(Ca) channels (i.e. NS309 and SKA-31) can inhibit myogenic tone in isolated resistance arteries, we hypothesized that this class of compounds may induce effective vasodilation in an intact vascular bed, such as the coronary circulation.
  
  
  RESULTS
  In a Langendorff-perfused, beating rat heart preparation, acute bolus administrations of SKA-31 (0.01-5 µg) dose-dependently increased total coronary flow (25-30%) in both male and female hearts; these responses were associated with modest, secondary increases in left ventricular (LV) systolic pressure and heart rate. SKA-31 evoked responses in coronary flow, LV pressure, and heart rate were qualitatively comparable to acute responses evoked by bradykinin (1 µg) and adenosine (10 µg). In the presence of apamin and TRAM-34, selective blockers of SK(Ca) and IK(Ca) channels, respectively, SKA-31 and bradykinin-induced responses were largely inhibited, whereas the adenosine-induced changes were blocked by ∼40%; TRAM-34 alone produced less inhibition. Sodium nitroprusside (SNP, 0.2 μg bolus dose) evoked changes in coronary flow, LV pressure, and heart rate were similar to those induced by SKA-31, but were unaffected by apamin + TRAM-34. The NOS inhibitor L-NNA reduced bradykinin- and adenosine-evoked changes, but did not affect responses to either SKA-31 or SNP.
  
  
  CONCLUSIONS
  Our study demonstrates that SKA-31 can rapidly and reversibly induce dilation of the coronary circulation in intact functioning hearts under basal flow and contractility conditions.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine,  University of Calgary, 3330 Hospital Dr. NW, Calgary, AB,  Canada T2N 4N1.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Mishra
authors.forename: Darrell
authors.initials: D
authors.lastname: Belke
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Braun
mesh_terms: D000818:Animals; D001030:Apamin / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole / Q000187:drug effects
chemical_list: D052160:Benzothiazoles; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; C411671:TRAM 34; C535212:naphtho(1,2-d)thiazol-2-ylamine; D009599:Nitroprusside; D001030:Apamin; D052250:Nitric Oxide Synthase Type III