Review ArticleThe kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins
Introduction
The interest for the kallikrein-kininogen-kinin system originates in the early experiments of Abelous and Bardier [1] who observed almost one century ago that the injection of an alcohol-insoluble fraction of human urine caused hypotension when injected i.v. into the anesthetized dog. Later, Frey [121] confirmed this first observation by i.v. injection of human or dog urine into dogs. The active compound responsible for the hypotensive effect was attributed to a specific substance named “F-substance” which was isolated from human urine [122], [194]. Kraut et al. [195] found that high concentrations of F-substance are present in the pancreas and it was thought that the pancreas was the main site of its synthesis. F-substance was then called “kallikrein”. Since that time glandular and plasma kallikrein have been shown to be specific activators of kininogens, kinins being responsible for the measured hypotensive effects.
The kallikreins, their precursors plasma prekallikrein and tissue prokallikrein, and kininogens have been isolated, characterized at the molecular and gene levels. Their tissue distribution and the mechanisms underlying the regulation of their expression have also been studied. Their behavior and their potential role in different pathologies have also been defined. The results of these investigations have recently been extensively reviewed [34], [74], [181], [234].
In 1949, Rocha e Silva et al. [318] have isolated bradykinin (BK) released from kininogens by the venom of Bothrops jararaca. Since that time, other kinins have also been characterized in different milieus and animal species. The nature of the enzymes responsible for their metabolism has been elucidated. The term “kininase” was then coined to define these inactivating enzymes. The mechanism of inactivation of kinins in plasma began with the characterization of carboxypeptidase N (kininase I) that releases the Arg residue from the carboxy-terminal end of BK, and kallidin (KD; Lys-BK) [111]. Afterwards, Yang and Erdös [414] isolated an enzyme (kininase II) that liberated the Phe8-Arg9 dipeptide of BK. Kininase II was later proved to be identical with the angiotensin I-converting enzyme (ACE) [415]. Additional kinin peptidases were thereafter identified and characterized such as carboxypeptidase M, neutral endopeptidase 24.11 and aminopeptidase P. The biologic effects of kinins are mediated by specific receptors. Kinin receptors have been classified according to the relative potencies of series of agonists and antagonists as proposed by Regoli and Barabé [309]. They stated that the B1-type of receptors for kinins are selectively sensitive to kinins lacking the carboxy-terminal Arg residue like des-Arg9-BK and Lys-des-Arg9-BK (des-Arg10-KD). On the other hand, the B2-type of receptors is optimally stimulated by the full sequence of BK, and Lys-BK (KD). The pharmacological characteristics, the nature of the second messengers and the regulation of these receptors have been extensively studied and the different results have been recently discussed by Hall [139] for the B2 receptor and by Marceau [228], [231] for the B1 receptor.
The synthesis of specific antagonists for both B1 and B2 receptors has brought some pharmacological evidence for the participation of BK and/or des-Arg9-BK in different pathophysiological processes, and also in their role in the beneficial cardiovascular effects of ACE inhibitors.
As for other peptides, different immunologic methods have been developed for the assessment of endogenous kinins, mainly BK. However, only a very low proportion of published papers dealing with kinins include the quantification of endogenous kinins. Moreover, and contrarily to other vasoactive peptides, the methods described in the literature for the measurement of kinins were not successfully developed commercially. The reasons for this lack of success appear to be the result of the nature of the peptides and also analytical difficulties linked to the BK, and des-Arg9-BK methodological pitfalls, lability of kinins, and autocrine and paracrine nature rather than endocrine activity.
The purpose of the present review is to describe the place of endogenous kinins, mainly BK, and des-Arg9-BK in the kallikrein-kininogen-kinin system, to review and compare the different methods reported for the assessment of endogenous kinins, to explain the difficulties and the pitfalls for their quantifications in biologic samples and finally to see how the results obtained by these methods could complement and extend the pharmacological evidence of their pathophysiological role.
Section snippets
Kallikreins
Plasma and tissue (glandular) kallikreins are the two most potent kininogenases known; however, they differ completely in their biochemical, immunologic and functional characteristics [34].
Analytical methods to measure endogenous kinins
In order to determine endogenous kinin levels in biologic fluids and tissues, different immunologic methods, mainly radioimmunoassays, have been developed. Due to the nature of these peptides and their lability to enzymes, sensitive and accurate measurement of endogenous kinins, B1 and B2 agonists, remains an important challenge.
Endogenous kinins in biologic milieus
Immunologic methods have been applied to the quantification of endogenous kinins in various biologic milieus. In this section, we will focus on plasma and urinary kinin measurements. The results obtained for other milieus will be described in the section devoted to the pathophysiological aspects.
Endogenous kinins as proinflammatory peptides
Considerable pharmacological evidence supports a role for BK, and des-Arg9-BK as endogenous mediators of inflammation. In fact, they induce an inflammatory response when injected exogenously into tissues. Their levels are elevated and related to the intensity of the inflammatory response. A specific inhibitor of their production inhibits dose-dependently both the local inflammatory response and the local concentration of the mediators. Alternatively, specific kinin antagonists of B1 and B2
Endogenous kinins as antihypertensive and cardioprotective peptides
Different experimental evidence points to a role of kinins, mainly BK, in the cardioprotective effects of ACE inhibitors. This evidence is mainly of pharmacological nature and has been obtained in hypertension, myocardial infarction, left ventricular hypertrophy and diabetes. These indirect findings which are sometimes conflicting (e.g. left ventricular hypertrophy) or incomplete, and have been recently extensively reviewed [214]. In this last section, we will focus on the various
Conclusion
The quantitative assessment of endogenous BK, and des-Arg9-BK has not only supported the pharmacological experimental results based on both B2 and B1 ligands, but has also shed new light on their pathophysiological roles.
In plasma, the reported concentrations of BK, and des-Arg9-BK are not readily comparable due to the fact that some of the immunologic methods have been poorly validated. These methods are often based on a single publication, without any further application. Moreover, other
Acknowledgements
C. Blais, Jr. is the recipient of a scholarship from the Fonds de la recherche en santé du Québec (FRSQ).
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