Document Detail

Vasodilation and mechanoenergetic inefficiency dominates the effect of the "Ca(2+)-sensitizer" MCI-154 in intact pigs.
MedLine Citation:
PMID:  12079638     Owner:  NLM     Status:  MEDLINE    
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. DESIGN: 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. CONCLUSION: 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.
Christian Korvald; Dag Ole Nordhaug; Tor Steensrud; Ebrahim Aghajani; Truls Myrmel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Scandinavian cardiovascular journal : SCJ     Volume:  36     ISSN:  1401-7431     ISO Abbreviation:  Scand. Cardiovasc. J.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-06-24     Completed Date:  2002-10-28     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9708377     Medline TA:  Scand Cardiovasc J     Country:  Norway    
Other Details:
Languages:  eng     Pagination:  172-9     Citation Subset:  IM    
Department of Thoracic and Cardiovascular Surgery, University Hospital Tromsø, Norway.
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MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
Calcium Channel Agonists / pharmacology*
Cardiac Output / drug effects
Cardiotonic Agents / pharmacology*
Cyclic Nucleotide Phosphodiesterases, Type 3
Dose-Response Relationship, Drug
Energy Transfer / physiology*
Heart Rate / drug effects
Myocardial Contraction / drug effects
Myocardium / metabolism
Oxygen Consumption / drug effects
Pyridazines / pharmacology*
Vascular Resistance / drug effects
Vasodilation / physiology*
Reg. No./Substance:
0/Calcium Channel Agonists; 0/Cardiotonic Agents; 0/Pyridazines; 98326-33-1/MCI 154; EC',5'-Cyclic-AMP Phosphodiesterases; EC Nucleotide Phosphodiesterases, Type 3
Comment In:
Scand Cardiovasc J. 2002 May;36(3):131-5   [PMID:  12079634 ]

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