The kinin system: suggestions to broaden some prevailing concepts

Abstract

The existence and importance of the kallikrein–kinin–kininase system, especially in the circulation, has taken over three-quarters of a century to be established. Finding the multiple components derived from renin–angiotensin and their functions stretched over a century [Erdös EG. Perspectives on the early history of angiotensin-converting enzyme—recent follow-ups. In: Giles TD, editor. Angiotensin-converting enzyme (ACE): clinical and experimental insights. Fort Lee: Health Care Communications; 2001, p. 3–16]. Although the discoveries were made independently, it was shown in 1970 that the angiotensin I-converting enzyme (ACE) is identical with kininase II, previously discovered by us, thus, a single protein can regulate either the activation or inactivation of the two peptide products. It followed that inhibitors of ACE can affect both processes [Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992;44:1–80]. After being engaged for a long time in characterizing the metabolism of various bio-active peptides, we, as well as others, noticed that the effect of ACE inhibitors go beyond simply blocking angiotensin (Ang) II release and bradykinin (BK) inactivation by the enzyme [Kaplan AP, Joseph K, Silverberg M. J Allergy Clin Immunol 2002:109(2):195–209; Yamada K, Erdös EG. Kidney Int 1982;22:331–1]. It also became apparent to us that in the complex multistep reactions needed to activate the kallikrein–kinin system, there should be some shortcuts—shunts—to accelerate and simplify important processes. Thus, some basic tenets developed after decades of intensive laboratory investigations—and by now generally accepted—can be challenged. For example, it should be considered that the activities of BK and Lys BK (kallidin) can be substantially different, and that sequentially linked reactions, starting with prokallikrein activation and leading to kinin release from kininogen and inhibition of kininases, may be only one way to activate kinin receptors. A summary of some suggested alterations on prevailing concepts is given below.