Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity.
Historically, the first described effect of an angiotensin converting enzyme (ACE) inhibitor was an increased activity of bradykinin, one of the substrates of ACE. However, in the subsequent years, molecular models describing the mechanism of action of ACE inhibitors in decreasing blood pressure and cardiovascular risk have focused mostly on the renin-angiotensin system. Nonetheless, over the last 20 years, the importance of bradykinin in regulating vasodilation, natriuresis, oxidative stress, fibrinolysis, inflammation, and apoptosis has become clearer. The affinity of ACE appears to be higher for bradykinin than for angiotensin I, thereby suggesting that ACE inhibitors may be more effective inhibitors of bradykinin degradation than of angiotensin II production. Data describing the effect of ACE inhibition on bradykinin signaling support the hypothesis that the most cardioprotective benefits attributed to ACE inhibition may be due to increased bradykinin signaling rather than to decreased angiotensin II signaling, especially when high dosages of ACE inhibitors are considered. In particular, modulation of bradykinin in the endothelium appears to be a major target of ACE inhibition. These new mechanistic concepts may lead to further development of strategies enhancing the bradykinin signaling.
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126, Pisa, Italy. stefano.taddei@med.unipi.it.
Stefano
S
Taddei
Heart Institute-Hypertension Unit, Medical School University of Sao Paulo, São Paulo, Brazil.
L
L
Bortolotto
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D012084:Renin-Angiotensin System / Q000187:drug effects; D012307:Risk Factors; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D000803:Angiotensin I; D001920:Bradykinin