Optimising conditions for studying the acute effects of drugs on indices of cardiac contractility and on haemodynamics in anaesthetized guinea pigs.
INTRODUCTION Assessment of cardiovascular functions in vivo is part of the core battery of guideline ICH S7A and is thereby required by regulatory authorities. The haemodynamic effects of repeated intravenous administrations of reference compounds were analyzed in order to validate the guinea pig model for safety pharmacology studies under GLP conditions. METHODS Male guinea pigs (n=54, weighing 565-762 g) were anaesthetized using 1.5 g/kg, i.p., urethane. Systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), heart rate (HR), left ventricular pressure (LVP), cardiac contractility (dp/dt(max)), and ECG (RR, QT, and QTc intervals) were recorded continuously. Animals received vehicle i.v. followed by cumulative doses of reference compounds. RESULTS Vehicle did not produce any relevant changes, either in cardiovascular or ECG parameters. Isoproterenol caused a rapid and significant increase in HR, LVP, and dp/dt(max), in contrast to a dose-dependent decrease in SAP and DAP. Epinephrine led to a potent increase in all cardiovascular parameters. Nifedipine produced a slight decrease in HR and LVP, and a potent decrease in blood pressure and dp/dt(max). Verapamil caused a dose-dependent decrease in all cardiovascular parameters. Ouabain resulted in a significant increase in SAP, DAP, LVP, and dp/dt(max); ECG showed an atrioventricular block and arrhythmia. Terfenadine, cisapride, and sotalol prolonged QT and QTc intervals, whereas vehicle and the other tested compounds did not produce any prolongation of the QTc interval. DISCUSSION Our results on HR, blood pressure, and ECG obtained after i.v. administration of reference compounds show the usefulness of the guinea pig in assessing cardiovascular safety. The anaesthetized guinea pig allows the measurement of cardiac contractility and the use of doses higher than in conscious animals. Using this animal model, several cardiovascular parameters can be recorded simultaneously at a modest cost in terms of test compound and the number of animals required.