title: Direct myocardial effects of OPC-18790 in human heart failure: beneficial effects on contractile and diastolic function demonstrated by intracoronary infusion with pressure-volume analysis.
abstract: OBJECTIVE
  We sought to determine the precise myocardial effects of OPC-18790 as demonstrated by intracoronary administration.
  
  
  BACKGROUND
  Although previous studies have determined the cardiovascular effects of a novel intravenous inotrope, OPC-18790, the observed benefits on contractile and diastolic function may have been confounded by the marked changes in peripheral loading associated with this drug when given intravenously.
  
  
  METHODS
  Eight heart failure patients received intracoronary OPC-18790 at 31.25 microg/min for 20 min, and then at 62.5 microg/min for another 20 min. Hemodynamic variables and pressure-volume indexes using the conductance catheter method were determined at baseline and then after the two doses.
  
  
  RESULTS
  There were no significant effects on heart rate, cardiac output or loading conditions, including afterload as determined by systemic vascular resistance and arterial elastance (Ea) and preload as determined by end-diastolic volume (EDV). There were significant increases in end-systolic elastance (Ees) from 0.74+/-0.11 to 0.90+/-0.16 mm Hg/ml at 31.25 microg/min and to 137+/-0.33 mm Hg/ml at 62.5 microg/min (p < 0.05 by analysis of variance [ANOVA]). Diastolic function improved, as determined by the time constant for isovolumetric relaxation tau, which decreased significantly from baseline to 31.25 microg/min (94+/-9 to 79+/-9 ms, p < 0.05), and did not shorten further at 62.5 microg/min (78+/-8 ms, p=NS). There were significant decreases in right atrial pressure (9+/-1 to 7+/-1 mm Hg, p < 0.01 by ANOVA) and mean pulmonary artery wedge pressure (21+/-3 to 16+/-2 mm Hg, p < 0.05 by ANOVA). This fall in filling pressures was not accompanied by any change in EDV. Inspection of the diastolic portion of the pressure-volume curve confirmed a downward shift consistent with pericardial release in five of the eight patients.
  
  
  CONCLUSIONS
  Intracoronary administration of OPC-18790 demonstrates that the direct myocardial effects of this agent include a modest increase in inotropy and improvement in diastolic function, both of which occur without increases in heart rate, indicating that this agent may be beneficial for the intravenous treatment of congestive heart failure.
authors.affiliation: Division of Cardiology, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: MacGowan
authors.forename: H L
authors.initials: HL
authors.lastname: Haber
authors.forename: T D
authors.initials: TD
authors.lastname: Cowart
authors.forename: C
authors.initials: C
authors.lastname: Tedesco
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: M D
authors.initials: MD
authors.lastname: Feldman
mesh_terms: D000368:Aged; D006328:Cardiac Catheterization; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003971:Diastole / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D013599:Systole / Q000187:drug effects; D016896:Treatment Outcome; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D015363:Quinolones; C077543:toborinone