Effect of milrinone on echocardiographic parameters after single dose in Beagle dogs and relationship with drug-induced cardiotoxicity.
The aim of this study was to further investigate the mechanism of development of cardiac lesions occurring under treatment with milrinone in dogs, by using echocardiography for assessing the effects of this drug on cardiac function. Milrinone is a cAMP phosphodiesterase 3 inhibitor having positive inotropic and vasodilatory effects. We treated groups of three dogs with milrinone at a single dose of 0.5 or 1 mg/kg and recorded M-mode and Doppler parameters at different time points before and after treatment. The hearts of the high-dose animals were histopathologically examined. The treatment with milrinone at 1 mg/kg produced mild cardiac lesions at two different locations. In the left ventricle, haemorrhages in the subendocardium and myocardium occurred in all three dogs. In the right atrium, subepicardial haemorrhages occurred in one dog and inflammation of the epicardium was observed in two dogs. These lesions were considered to be related to changes in the cardiac function, which were investigated by echocardiography. Milrinone treatment produced a moderate tachycardia and changes in M-mode parameters indicating an increase in contractility, in particular, a decrease in end-systolic volume, an increase in ejection fraction and an increase in the rate of circumferential fiber shortening. In addition, there was an increase in the maximal aortic flow velocity evaluated by Doppler measurements, which is thought to represent a haemodynamic correlate of an increase in left ventricular contractility. This increase in myocardial work is considered to play a key role in the development of the lesions observed in the left ventricle. Doppler measurements also revealed changes in the right atrioventricular flow, probably resulting from cardiac stimulation produced by milrinone. In particular, there was an increase in the Vmax of the A-wave of the tricuspid flow, suggesting an increase in contractility of the right atrium. This change, by increasing blood flow in atrial wall, may be involved in the induction of the lesions observed in the right atrium. In conclusion, Doppler and M-mode echocardiography are useful tools to assess haemodynamic changes occurring upon treatment with vasodilators or cardiac stimulants in order to further understand the mechanism of development of cardiac lesions produced by such compounds.
Hanton
Gilles
G
Department of Toxicology and Comparative Medicine, Pfizer Global Research and Development, Z.I. Pocé-sur-Cisse, BP 159, F-37401 Amboise Cedex, France. gilles.hanton@pfizer.com
Gautier
Mathieu
M
Bonnet
Pierre
P
Herbet
Aurelia
A
D000284:Administration, Oral; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004452:Echocardiography; D006325:Heart Atria / Q000473:pathology; D006331:Heart Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006470:Hemorrhage / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D020105:Milrinone / Q000633:toxicity*; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D018608:Ultrasonography, Doppler; D016277:Ventricular Function, Left / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D020105:Milrinone