Dose-response of benazepril on biomarkers of the classical and alternative pathways of the renin-angiotensin-aldosterone system in dogs

Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin-angiotensin-aldosterone system (RAAS); however, the dose-dependent effects of benazepril on comprehensive RAAS components remain unknown. In this study, nine purpose-bred healthy dogs received three different dosages of oral benazepril (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) in a randomized crossover design following induction of RAAS activation by consuming a low-sodium diet. Blood samples were collected at serial time intervals after benazepril dosing to measure plasma benazeprilat (active metabolite of benazepril) and serum RAAS biomarkers. Blood pressure and echocardiogram were performed at baseline and after each benazepril administration. Time-weighted averages for RAAS biomarkers for 12 hours post-dose and hemodynamic variables were compared between dosing groups using Wilcoxon rank-sum testing. Compared to the lowest dosage of benazepril (0.125 mg/kg), the highest dosage (0.5 mg/kg) resulted in lower time-weighted average values of angiotensin (Ang) II (-38%, P = 0.004), Ang1-5 (-53%, P = 0.001), ACE-S (surrogate for ACE activity; -59%, P = 0.0002), and ALT-S (surrogate for alternative RAAS activity; -22%, P = 0.004), and higher values of AngI (+ 78%, P = 0.014) and PRA-S (surrogate for plasma renin activity; +58%, P = 0.040). There were no relevant differences between dosing groups for blood pressure or echocardiographic variables. Knowledge of dose-dependent alterations in biomarkers of the classical and alternative RAAS pathways could help inform clinical trials for dosage optimization in both dogs and humans.