Comparative effects of R 80122, enoximone, and milrinone on left ventricular phosphodiesterase isoenzymes in vitro and on contractility of normal and stunned myocardium in vivo in dogs.
Using different subtypes of cyclic nucleotide phosphodiesterase (PDE) isoenzymes isolated from canine left ventricle, we identified R 80122, a 1,2,3,5-tetrahydro2-oxoimidazo[2,1-b]quinazoline derivative that was a more selective and potent inhibitor of PDE type III than milrinone or enoximone. Such substances improve cardiac contraction and relaxation, elicit vasodilation, and increase cardiac output (CO). To determine the extent to which these compounds affect the contractile force of stunned myocardium, the effects of enoximone, milrinone, and R 80122 on cardiac function were compared in anesthetized dogs subjected to 15-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion, and treated beginning 30 min after reperfusion, with the compound being studied. During occlusion, all dogs exhibited passive systolic ventricular wall bulging in the ischemic area. Thirty minutes after reperfusion, systolic wall thickening was significantly decreased in the reperfused LAD segments and remained low (at 36% of baseline) in control animals. After enoximone administration, global left ventricular (LV) function was improved with i.v. doses greater than or equal to 0.64 mg/kg. Systolic wall thickening in the ischemic myocardium was restored less than or equal to 70% of baseline at 1.25 mg/kg i.v., but this dose also induced a marked decrease in arterial pressure and an increase in heart rate (HR). Milrinone and R 80122 significantly increased global LV function and systolic wall thickening in ischemic areas at doses greater than or equal to 0.16 mg/kg i.v. At the highest doses, HR increased slightly with both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
Vandeplassche
G M
GM
Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Hermans
C F
CF
de Chaffoy de Courcelles
D R
DR
D'Aubioul
J A
JA
Wouters
L J
LJ
De Clerck
F F
FF
D000704:Analysis of Variance; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D017335:Enoximone; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*
D002316:Cardiotonic Agents; D007093:Imidazoles; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011799:Quinazolines; C076518:R 80122; D017335:Enoximone; D010727:Phosphoric Diester Hydrolases; D020105:Milrinone