title: Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts.
abstract: BACKGROUND
  Cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally identified as a delta-protein kinase C inhibitor, has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin mitigates deleterious effects associated with CP/CPB.
  
  
  RESULTS
  Langendorff-perfused isolated rat hearts were subjected to 2 hours intermittent cold (10°C) CP (St Thomas II) followed by 30 minutes normothermic reperfusion. CP was delivered every 30 minutes for 1 minute. Hearts were treated with rottlerin 1 μmol/L (CP+R) (n=7) or without rottlerin (CP) (n=9), and the BK(Ca++) channel inhibitor paxilline 100 nmol/L was supplied in the CP. Hearts constantly perfused with KHB served as controls (n=6). Baseline parameters of cardiac function were similar between groups. CP resulted in reduced cardiac function (left ventricular diastolic pressure, 39 ± 3.8%; ± dP/dt, 32 ± 4.4%, -41 ± 5.1% decrease compared to baseline). Treatment with rottlerin 1 μmol/L significantly improved CP-induced cardiac function (left ventricular diastolic pressure, 20 ± 5.9%; ± dP/dt, 5.2 ± 4.5%, -11.6 ± 4.7% decrease versus baseline; P<0.05 CP+R versus CP). Rottlerin also caused a significant increase in coronary flow postreperfusion (CP, 34 ± 4.2% decrease from baseline; CP+R, 26 ± 9.6% increase over baseline; P=0.01). Independent of vascular effects, CP significantly decreased isolated myocyte contraction, which was restored by rottlerin treatment. The BK(Ca++) channel inhibitor greatly reduced the majority of beneficial effects associated with rottlerin.
  
  
  CONCLUSIONS
  Rottlerin significantly improves cardiac performance after CP arrest through improved cardiomyocyte contraction and coronary perfusion.
authors.affiliation: Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital and Alpert Medical School, Brown University, Coro 5.230, 1 Hoppin St, Providence, RI 02903, USA. rclements2@lifespan.org
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Brenda
authors.initials: B
authors.lastname: Cordeiro
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000098:Acetophenones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D003080:Cold Temperature; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006324:Heart Arrest, Induced / Q000379:methods*; D007211:Indoles / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051745:Protein Kinase C-delta / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007211:Indoles; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C048220:paxilline; C085746:rottlerin; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta