title: Rottlerin-induced BKCa channel activation impairs specific contractile responses and promotes vasodilation.
abstract: BACKGROUND
  Activation of large conductance calcium-activated potassium (BKCa) channels is cardioprotective for ischemic injury and can enhance vasorelaxation. Rottlerin has recently been identified as a potent BKCa activator. We demonstrated that rottlerin improves cardiac function and increases coronary flow when used as a cardioplegia additive in rat and mouse models of cardioplegic arrest and reperfusion. In this study we examined the effectiveness and specificity of the putative BKCa activator rottlerin on vascular reactivity in response to specific contractile and dilatory agonists.
  
  
  METHODS
  Aortic rings from wild-type (wt) and BKCa knock-out (KO) mice were mounted in a tissue bath with force transducers. The vasodilatory effect of rottlerin was evaluated after pre-constriction with U46619. Dose responses to the contractile agonists U46619 and phenylephrine (PE), and vasodilation responses to rottlerin, hydrogen sulfide (H2S), and sodium nitroprusside (SNP) were performed after pretreatment with rottlerin. Similar studies were performed in pig coronary vessels.
  
  
  RESULTS
  The BKCa KO mouse aortic rings exhibited spontaneous contraction and had greater contractile responses to U46619 and reduced vasodilation to SNP compared with wt mice. The wt and KO responses to phenylephrine were similar. Rottlerin dose dependently dilated wild-type vessels, but not in BKCa KO animals. Pretreatment with rottlerin caused depressed U46619 responses, but had no effect on PE, SNP, or H2S-mediated responses. However, pig coronary vessels pretreated with rottlerin exhibited reduced contractile responses and enhanced nitric oxide-dependent dilation.
  
  
  CONCLUSIONS
  Rottlerin directly causes vasodilation through BKCa channel dependent mechanisms. The BKCa channel activator pretreatment enhances vasodilatory responses and impairs specific vasoconstrictive agonists.
authors.affiliation: Cardiothoracic Surgery Research/Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital and Warren Alpert Medical School, Brown University, Providence, Rhode Island.
authors.forename: Brenda
authors.initials: B
authors.lastname: Cordeiro
authors.affiliation: Cardiothoracic Surgery Research/Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital and Warren Alpert Medical School, Brown University, Providence, Rhode Island.
authors.forename: Connor
authors.initials: C
authors.lastname: Shinn
authors.affiliation: Cardiothoracic Surgery Research/Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital and Warren Alpert Medical School, Brown University, Providence, Rhode Island.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
authors.affiliation: Cardiothoracic Surgery Research/Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital and Warren Alpert Medical School, Brown University, Providence, Rhode Island. Electronic address: richard_clements@brown.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000503:physiopathology*; D001578:Benzopyrans / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000098:Acetophenones; C530995:BKCa protein, mouse; D001578:Benzopyrans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; C085746:rottlerin