In vivo endothelial interaction between ACE and COX inhibitors

Here we studied the mechanism of thrombolytic response (THR) induced by angiotensin converting enzyme (ACE-I) in vivo in anaesthetised Wistar rats with extracorporeal circulation. Intravenous injections of ACE-Is, i.e. perindopril or quinapril at non-hypotensive doses of 3–30 μg kg −1 produced a dose-dependent thrombolysis that was associated with a parallel rise in arterial blood levels of 6-keto-PGF 1α, but not those of TXB 2 or PGE 2. L-NAME at a dose of 5 mg kg −1 affected significantly neither ACE-I-induced thrombolysis nor prostacyclinemia; however, the pre-treatment with icatibant (0.1–0.5 mg kg −1) abolished both effects. The selective COX-1 inhibitor, SC 560 (100–300 μg kg −1 i.v.), or a would be selective COX-3 inhibitor—paracetamol (acetaminophen, 1–3 mg kg −1), both agents induced a transient thrombolysis and slightly potentiated thrombolysis by ACE-Is. In contrast, selective COX-2 inhibitors (rofecoxib⪢celecoxib>nimesulide>NS 398) were thrombogenic, and abolished THR and rise in 6-keto-PGF 1α induced by ACE-Is. Summing up, in our in vivo bioassay system ACE-Is such as quinapril, perindopril or captopril at non-hypotensive doses evoke THR that is mediated by endogenous bradykinin and prostacyclin derived from endothelial COX-2.