Comparative preclinical assessment of angioedema risk of inhibitors of renin‐angiotensin system and neprilysin in the anesthetized rat tracheal plasma extravasation assay

Abstract

Angiotensin converting enzyme inhibitors (ACEi) and dual acting ACEi‐neprilysin (NEP) inhibitors are associated with risk of angioedema in the clinic. In the present study, we used a rodent model to assess the angioedema risk of administration of angiotensin receptor blocker (ARB) and NEP inhibitor, dosed alone or in combination, at antihypertensive doses. Intravenous effects (mg/kg) of ACEi (lisinopril, LIS 0.03‐10), ACEi‐NEPi (omapatrilat, OMPT‐0.03‐10; ilepatril, ILPT‐0.3‐30), AT1 antagonist (valsartan VAL‐0.3‐10), neprilysin inhibitor (CGS‐24592, CGS‐0.3‐30) or a combination (AT1‐NEPi) and vasodilator‐ sodium nitroprusside (SNP) on tracheal plasma extravasation (TPE) was tested in anesthetized rat (Sulpizio et al., JPET 309:1411,2004). Treatment with LIS, OMPT, ILPT or ACEi‐NEPi (LIS + CGS) resulted in a significant, dose related increases in TPE (peak values 48, 91, 89 and 57 ng/mg respectively vs. 1‐10 ng/mg, vehicle). Pretreatment with HOE 140 (bradykinin B2 antagonist, 30 ìg/kg, iv) completely antagonized TPE observed with LIS, OMPT and ILPT. In contrast, VAL, CGS, VAL+CGS combination or SNP treatment produced no increase in TPE. These results indicate that unlike ACEi or ACEi‐NEPi, ARB or ARB‐NEPi did not result in increased TPE (hence carry minimal or no risk of angioedema). Additionally, bradykinin mediated angioedema risk can be reliably detected pre‐clinically using this simple assay.