Hypertension study in anaesthetized rabbits: protocol proposal for AT1 antagonists screening

Abstract

Introduction: The aim of this study was to establish an optimized fast and safe protocol for the pharmacological screening of AT1 antagonists. Materials and methods : The pharmaceutical prototype AT1 antagonist losartan, its active metabolite EXP3174 and the synthetic compound MMK1 were analysed in order to validate the protocol. Ang II was continuously infused while the animals received the drugs in two procedures. Results: In the post-treatment procedure drugs were administered either in a single bolus dose or in a sequential manner. When losartan was administered in a single bolus dose, efficacy was evident until the 7th min ( p=0.012) whilst EXP3174 infusion extended the efficiency up to the end of the study ( p=0.006). In addition, the sequential injections of losartan prolonged the inhibitory time interval until the end of the study ( p=0.045). In the pre-treatment procedure, results suggested a dose-dependent inhibitory effect for both antagonists. The pressor response to Ang II was unchanged after MMK1 administration either in the post- or in the pre-treatment mode. Conclusions: The proposed protocol appears to be safe, simple and fast for the pharmacological screening of AT1 antagonists and enables the evaluation of new antagonists using lower doses than any other reported in the literature.