Characterisation of rodent dobutamine echocardiography for preclinical safety pharmacology assessment

Abstract

Introduction Dobutamine stress echocardiography (DSE) is performed to detect subtle ischemic regions in the myocardium in patients suffering from stenosed coronary artery disease. While in a clinical and veterinary context DSE is performed daily, in the preclinical context, a very limited application has been described in the literature. In the drug development process, the safety of new chemical entities on the cardiovascular system is a primary requirement for the development of new agents/drugs for administration in humans. There are limited tools to evaluate the impairment of myocardial performance and cardiac contractility in preclinical species and particularly in rodents. In this present paper a possible imaging application is presented. Methods Anesthetised male Crl:CD(SD) rats ( n = 14) were given single intravenous doses of vehicle (5% w/v Dextrose solution) and dobutamine hydrochloride at 10 μg/kg/min. Echocardiography was performed, starting immediately before the infusion and animals were monitored up to 5 min after the end of infusion. Standard and non-standard echocardiography parameters were evaluated to detect test article related changes compared to vehicle infused animals. Results Thickening of left ventricle walls and interventricular septum and increased velocity of circumferential stress were observed in dobutamine infused animals compared to those receiving vehicle. These changes were considered to be a direct effect on myocardial contractility, as also confirmed by increased functional parameters (i.e., Ejection Fraction, End Diastolic Volume and decrease of the ratio between pre-ejection period and ejection time of the aortic flow). In dobutamine infused rats the “Tei index” increased up to approximately 32% compared to vehicle animals, showing a clear relationship with increased contractility. Discussion As expected dobutamine infusion in the anaesthetised rat is capable of inducing a positive inotropic effect and echocardiography results are a reliable tool for the determination of changes in contractility induced by pharmacological stress testing in the rat.