title: Vasodilation and mechanoenergetic inefficiency dominates the effect of the "Ca(2+)-sensitizer" MCI-154 in intact pigs.
abstract: OBJECTIVE
  Ca(2+)-sensitizing agents hold potential as ideal cardiac inotropes, but effects in intact animals are scarcely described. We evaluated a pyridazinone derivative, MCI-154, for hemodynamic, inotropic, mechanoenergetic and oxidative metabolic effects.
  
  
  METHODS
  Intracavitary left ventricular (LV) pressure and conductance (volume) was assessed in open chest anesthetized pigs (n = 6). Contractile performance, pressure-volume area (PVA) and myocardial oxygen consumption (MVO(2)) were assessed. Myocardial substrate uptake and production of (14)CO(2 )(from glucose) and (3)H(2)O (from fatty acids) were monitored. MCI-154 administration: "low range": 0.1, 0.2, 0.3, 0.5 microg/kg/min and "high range": 0.75, 1.0, 2.0, 3.0 microg/kg/min. Parameters were compared with baseline and a time reference group (n = 7).
  
  
  RESULTS
  MCI-154 induced a progressive dose-dependent decrease in systemic vascular resistance, with a concomitant increase in heart rate and cardiac output. Contractility increased only in the high-dose range, and mechanoenergetic efficiency was significantly reduced by drug infusion in all doses.
  
  
  CONCLUSIONS
  The pyridazinone derivative MCI-154 has minimal inotropic action, induces a significant "oxygen waste", and decreases vascular resistance in intact pigs. A potent phosphodiesterase inhibitory effect may explain this, which suggests further drug refinement.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Hospital Tromsø, Norway. christian.korvald@rito.no
authors.forename: Christian
authors.initials: C
authors.lastname: Korvald
authors.forename: Dag Ole
authors.initials: DO
authors.lastname: Nordhaug
authors.forename: Tor
authors.initials: T
authors.lastname: Steensrud
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Aghajani
authors.forename: Truls
authors.initials: T
authors.lastname: Myrmel
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004305:Dose-Response Relationship, Drug; D004735:Energy Transfer / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology*
chemical_list: D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D011724:Pyridazines; C052228:MCI 154; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3