Is there a role for bradykinin in the therapeutic and side effects of angiotensin-converting enzyme inhibitors?

OBJECTIVE

To review critically the persistent suggestion that at least a part of the beneficial and side effects of angiotensin I converting enzyme inhibitors (ACEIs) is derived from the potentiation of endogenous bradykinin (BK).

DATA SOURCES

Selected clinical studies of the pharmacology and analytical biochemistry of the kallikrein-kinin system, current literature on novel drugs binding to receptors for BK and angiotensin II, and a few animal studies when clinical data were not available.

DATA EXTRACTION

Current concepts of the kallikrein-kinin system and related analytical/pharmacological tools are briefly reviewed and applied to the analysis of the role of endogenous kinins in the therapeutic and side effects of ACEIs.

DATA SYNTHESIS

The development of effective BK antagonists is recent and provides novel opportunities to assess the role of BK in physiology and pathology. The role of BK as an inflammatory mediator is relatively well understood, and current drug development programs for kinin receptor agonists and antagonists are focused on the inflammatory pharmacological profile of kinins. The kallikrein-kinin system may not be active to a significant degree in normal individuals, but rather recruited during tissue injury or by specific physiological conditions (such as high sodium intake). The role of BK in some inflammatory/anaphylactoid side effects of ACEIs is not firmly established, but possible. The role of BK in the therapeutic effects of ACEIs depends on the model in animal studies and is likely to be modest in essential hypertension.

CONCLUSION

Several methodological problems have delayed the progress of clinical research of the kallikrein-kinin system. While ACEIs clearly potentiate the tissue effects of exogenous BK, the role of endogenous BK in the normal and pathological circulation is still uncertain.