title: Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.
abstract: BACKGROUND
  Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys.
  
  
  METHODS
  The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a β-blocker), or dl-sotalol (a β+IKrblocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug).
  
  
  RESULTS
  Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both β-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure.
  
  
  CONCLUSIONS
  The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan. Electronic address: ishizaka.tomomichi.du@daiichisankyo.co.jp.
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Ishizaka
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yoshimatsu
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mori
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects* / Q000494:pharmacology; D000758:Anesthesia / Q000379:methods; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D008790:Metoprolol / Q000009:adverse effects / Q000494:pharmacology; D020105:Milrinone / Q000009:adverse effects / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D012307:Risk Factors; D013015:Sotalol / Q000009:adverse effects / Q000494:pharmacology; D017725:Ventricular Pressure / Q000187:drug effects* / Q000502:physiology
chemical_list: D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D013015:Sotalol; D008790:Metoprolol; D020105:Milrinone
keywords: Inotrope; Load-independence; Lusitrope; Monkeys; Pressure-volume loop