Section Review Cardiovascular & Renal: Bradykinin degradation: potential pathways for cardiovascular therapeutic use

Abstract

Bradykinin (BK) is a widely distributed nine amino acid peptide with potent cardiovascular effects. Physiologically, BK has a very brief duration of action due to rapid metabolism by a number of widely distributed enzymes, including carboxypeptidase N, angiotensin converting enzyme (ACE), endopeptidase 24.11 (EP24.11), en-dopeptidase 24.15 (EP24.15), and aminopeptidase P. The physiological importance of BK in cardiovascular regulation is beginning to be recognised, due to the development of inhibitors of these BK-degrading enzymes. ACE inhibitors have been used in clinical practice for a number of years for the treatment of cardiovascular diseases, but it has only been recognised recently that their beneficial effects are due to preservation of endogenous BK from metabolism, as well as by prevention of angiotensin II production. Inhibitors of EP24.11 have been tested in various animal models of cardiovascular diseases, and in human patients, and have been shown to have limited benefit when given alone. When combined with ACE inhibitors, however, the effects are synergistic. A combination of inhibitors of ACE, EP24.11, and EP24.15 has been shown to have greater efficacy than a combination of ACE and EP24.11 inhibitors in an animal model of myocardial ischaemia/reperfusion injury. These studies suggest that inhibition of a single BK-degrading enzyme will not provide maximal protection of BK from degradation if metabolism is simply shifted to other enzymes, and that a combination of inhibitors would be preferable to an inhibitor of a single enzyme. Individual drugs which inhibit multiple BK-degrading enzymes are underdevelopment and have been shown to have advantages over inhibitors of a single enzyme pathway. The evidence presented in the following review suggests that inhibitors of BK metabolism appear to have promise in the treatment of cardiovascular diseases such as hypertension, congestive heart failure, and ischaemia/reperfusion injury.

Key Words:

• aminopetidase-P
• angiotensin converting enzyme inhibitors
• bradykinin degradation
• carboxypeptidase N
• endopeptidases 24.11 & 24.15
• heart failure
• hypertension