title: Use of M-mode and Doppler echocardiography to investigate the cardiotoxicity of minoxidil in beagle dogs.
abstract: Doppler and M-mode echocardiography (EC) were used to investigate the effects of minoxidil on the cardiac function of the dog and potentially to clarify the pathogenesis of cardiac lesions, in particular the necrotic lesion in the left ventricle and the haemorrhagic lesion in the right atrium. Groups of three dogs were treated with a single oral dose of 0.5 or 2 mg/kg minoxidil or control vehicle, and M-mode and Doppler parameters were recorded at different time points before as well as 1, 3 and 24 h after treatment. The treatment produced a number of changes in M-mode parameters that indicate an increase in left ventricle contractility, in particular, increases in the percentage of thickening of the left ventricle wall during systole and in ejection fraction, and decrease of systolic volume. There was also a decrease in diastolic volume, which indicates a decrease in filling of the left ventricle probably due to the tachycardia and subsequent decrease in inter-systolic time. Doppler EC showed an increase in the velocity of the aortic flow, which indicates an increase in cardiac contractility. There was also a mild increase in stroke volume, which together with the tachycardia resulted in a marked increase in cardiac output. Together, Doppler and M-mode recordings gave evidence of an increase in the contractility of the left ventricle. This change is consistent with the generally accepted mechanism for the development of the left ventricle lesion induced by minoxidil. Minoxidil also produced changes in atrio-ventricular flows. The velocity and/or acceleration of E- and A-waves of the mitral and tricuspid flows increased, and the E/A ratio decreased. The changes in the E-wave indicate a faster diastole of the ventricle probably to compensate for the decrease in inter-systolic time. The changes in A wave are characteristic of an increased amplitude and velocity of the atrial contraction. This latter change is much more marked for tricuspid than for mitral flow. For both flows the E/A ratio decreased, which indicates that the contraction of the atria plays an increased role in ventricle filling after minoxidil treatment. This stimulation of atrial contraction that we evaluate with Doppler EC may play a key role in the development of the atrial lesion produced by minoxidil. The fact that the change is more marked in the right than in the left atrium may explain why the lesion occurs only in the right atrium in dogs. This study showed, therefore, that Doppler EC associated with M-mode EC is a useful method for obtaining pertinent information on the pathogenesis of the left ventricle lesion induced by haemodynamic mechanisms. Moreover, Doppler EC allowed the assessment of changes in the function of the right atrium that may be involved in the development of the right atrial lesion.
authors.affiliation: Pfizer Global Research and Development, Z.I. Pocé-sur-Cisse, BP 159, 7401 Amboise Cedex, France. gilles.hanton@pfizer.com
authors.forename: Gilles
authors.initials: G
authors.lastname: Hanton
authors.forename: Mathieux
authors.initials: M
authors.lastname: Gautier
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography / Q000379:methods / Q000662:veterinary*; D018619:Echocardiography, Doppler, Pulsed / Q000379:methods / Q000662:veterinary*; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D008297:Male; D008914:Minoxidil / Q000008:administration & dosage / Q000633:toxicity*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000633:toxicity*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D014665:Vasodilator Agents; D008914:Minoxidil