Chronically Instrumented Conscious Dog Model in Cardiovascular Toxicology Studies

A chronically instrumented dog model has been developed to conduct preclinical studies of the cardiovascular pharmacology and toxicology of pharmaceuticals. Eight conscious, unrestrained dogs can be simultaneously studied while cardiovascular signals are acquired through the use of flexible tethers, sealed mercury rotary connectors, and digital data acquisition and analysis systems. Test articles can be administered by either oral or intravenous routes. Intravenous infusions are performed via indwelling cannulae and remote controlled infusion pumps. The principle of operation is explained for implantable micromanometers, and sonomicrometers as well as electromagnetic, transit time, and Doppler blood flowmeters. Historical references are provided for the development of several of these devices. Techniques are described to perform aseptic thoracotomy surgery and to implant devices to measure cardiac left ventricular and aortic blood pressure, left ventricular wall thickness or segment length, and blood flow through the circumflex branch of the left main coronary artery. A procedure for in vivo calibration of implantable pressure transducers is described. Compared to acute anesthetized dog experiments, the data provided by these chronically instrumented conscious dogs are likely to be more predictive of a drug's effect in conscious humans and the number of experimental animals required is substantially reduced.