In Vivo Methods in Cardiovascular Safety Pharmacology

Cardiovascular safety pharmacology (SP) studies aim to define the proarrhythmic risk of a new chemical entity (NCE) and examine its potential effects on the heart and peripheral vasculature as well as assess any other effect that may secondarily lead to an activation or depression of cardiovascular performance. According to the cardiovascular SP guidelines, telemetry studies in conscious large animals are preferred for evaluation of drug-induced effects on systemic arterial pressure, left ventricular pressure, and electrocardiography. However, telemetry studies in small animals can be invaluable as part of the lead optimization. It is important to recognize that rats should not be used to evaluate the drug effect in ventricular repolarization as they have different mechanisms of ventricular repolarization, compared to humans, large mammals, and guinea pigs. The main advantage of telemetry studies is that they are performed under unstressed and physiological conditions. Despite the preference for the use of conscious animals, SP studies are also performed using anesthetized animal models. Anesthetized animal studies allow for a more in-depth evaluation of possible drug effects on the heart and vascular function in a model with a highly stable hemodynamic state and very low variability of the measured parameters. However, consideration should be given to the potential influence of the anesthesia on the parameters measured. SP studies should also evaluate whether new chemical entities can impair the autonomic nervous system by assessing the baroreflex sensitivity (BRS) or heart rate variability. In this chapter, we highlight in vivo methods used in cardiovascular SP, including both conscious and anesthetized animal models.