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 microg kg(-1) produced a dose-dependent thrombolysis that was associated with a parallel rise in arterial blood levels of 6-keto-PGF(1 alpha), 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 microg 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(1 alpha) 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.
Gryglewski
R J
RJ
Jagiellonian Medical Research Centre, Department of Experimental Pharmacology, Jagiellonian University, Poland 17 Slawkowska, 31-016 Cracow, Poland. mfgrygle@cyf-kr.edu.pl
Chlopicki
S
S
Swies
J
J
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000502:physiology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy
D000806:Angiotensin-Converting Enzyme Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001920:Bradykinin