Vasodilation and mechanoenergetic inefficiency dominates the effect of the "Ca(2+)-sensitizer" MCI-154 in intact pigs.
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.
Korvald
Christian
C
Department of Thoracic and Cardiovascular Surgery, University Hospital Tromsø, Norway. christian.korvald@rito.no
Nordhaug
Dag Ole
DO
Steensrud
Tor
T
Aghajani
Ebrahim
E
Myrmel
Truls
T
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*
D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D011724:Pyridazines; C052228:MCI 154; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3