title: Characterization of an investigative safety pharmacology model to assess comprehensive cardiac function and structure in chronically instrumented conscious beagle dogs.
abstract: BACKGROUND
  There has been an increasing need to conduct investigative safety pharmacology studies to complement regulatory-required studies, particularly as it applies to a comprehensive assessment of cardiovascular (CV) risk.
  
  
  METHODS
  We describe refined methodology using a combination of telemetry and direct signal acquisition to record concomitant peripheral hemodynamics, ECG, and left ventricular (LV) structure (LV chamber size and LV wall thickness) and function, including LV pressure-volume (PV) loops to determine load independent measures of contractility (end systolic elastance, Ees, and preload recruitable stroke work, PRSW) in conscious beagle dogs. Following baseline characterization, 28days of chronic rapid ventricular pacing (RVP) was performed and cardiac function monitored: both as a way to compare measures during development of dysfunction and to characterize feasibility of a model to assess CV safety in animals with underlying cardiac dysfunction.
  
  
  RESULTS
  While ±dP/dT decreased within a few days of RVP and remained stable, more comprehensive cardiac function measurements, including Ees and PRSW, provided a more sensitive assessment confirming the value of such endpoints for a more clear functional assessment. After 28days of RVP, the inodilator pimobendan was administered to further demonstrate the ability to detect changes in cardiac function. Expectedly pimobendan caused a leftward shift in the PV loop, improved ejection fraction (EF) and significantly improved Ees and PRSW.
  
  
  CONCLUSIONS
  In summary, the data show the feasibility and importance in measuring enhanced cardiac functional parameters in conscious normal beagle dogs and further describe a relatively stable cardiac dysfunction model that could be used as an investigative safety pharmacology risk assessment tool.
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Stump
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Detwiler
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Hillary K
authors.initials: HK
authors.lastname: Regan
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Gilberto
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: DeGeorge
authors.affiliation: Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sannajust
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D004567:Electrodes, Implanted; D006334:Heart Function Tests / Q000379:methods* / Q000592:standards*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D010600:Pharmacology / Q000379:methods*; D011724:Pyridazines / Q000494:pharmacology; D018570:Risk Assessment; D012449:Safety; D013686:Telemetry / Q000379:methods*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D011724:Pyridazines; C041648:pimobendan
keywords: Beagle dog; Cardiac contractility; Cardiac dysfunction; Cardiac function; Heart failure; ICH S7A; Pressure volume loop; dP/dT