Search

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 10μg/kg/min. Echocardiography was performed, starting immediately before the infusion and animals were monitored up to 5min 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. [Copyright &y& Elsevier]

Abstract: Introduction: Telemetry represents the gold standard technique for the acquisition of animal haemodynamic signals in the pharmaceutical preclinical development of new chemical entities. In terms of electrocardiographic signal recording, the quality is well established in large animals, mainly dog, non human primates and minipig, whereas it is still lacking in terms of satisfactory results in rodents (mouse and rat in particular). In very recent times, an increasing interest in early safety prediction for the reduction of cardiovascular attrition has been raised in all the major pharmaceutical companies, focusing in particular, on in vivo models. Methods: Crl:CD(SD) and Wistar Han rats (Crl:WI[Han], Charles River) underwent surgery for the implantation of telemetry devices (Data Science International, USA) for the acquisition of blood pressure and electrocardiogram (ECG). A group of male CD rats (N =6) was implanted using the standard procedure as described by DSI technical documentation; another male CD group (N =3) was implanted using the technique described by Sgoifo et al. (1996); a third group (total of N =46, N =26 male CD rats, and N =10 male WI and N =10 female WI) was implanted using an alternative approach developed in our laboratory. Results: The new surgical procedure was analysed based on technical difficulties, time to complete the surgery, time to recover, animal care, survival time after surgery and quality of telemetry signal recordings. Although a quantitative and qualitative comparison with other techniques described in literature was beyond the scope of the present work, based on our laboratory experience, Sgoifo''s methodology showed better results compared to DSI standard approach, but surgical procedure was not easy to perform and more invasive. The novel approach described in the present paper was characterised by simplicity, repeatability, high rate of survival and improved quality of ECG signals for all the implanted rats. Discussion: Telemetry in small rodents became of particular interest in the early safety assessment of cardiovascular liability during the development of new chemical entities. Although several surgical procedures are well described in literature, none seem to offer high standard electrocardiography signals in order to reliably detect intervals or arrhythmias. In the Safety Pharmacology Laboratory at GlaxoSmithKline, Verona (Italy), a novel and alternative surgical placement of the electrocardiographic electrodes in Lead II configuration was developed, in the rat. The scope of the present paper is to illustrate that this alternative surgical procedure is easily reproducible, minimally invasive and gives high standard quality ECG signals. [Copyright &y& Elsevier]