Historical Background

Emil-Karl Frey, Eugen Werle, and Heinrich Kraut (left to right)

The surgeon Emil-Karl Frey, a scholar of the famous ‘Geheimrat’ Ferdinand Sauerbruch, observed in 1925 a considerable reduction in arterial blood pressure when he injected human urine into dogs. Unlike many other contemporary scientists he did not attribute this effect to a toxic action of urine, but rather as the specific activity of an unknown substance with potential biological functions (Frey, 1926; Frey and Kraut, 1926): “It is a substance that probably originates from several organs, is eliminated by the kindneys and has a pronounced cardioactive and vasoactive effect: a substance that is assigned the role of a hormone in the organism”. This F-substance was then called kallikrein, since it was considered to have originated in the pancreas (Greek synonym: kallikreas) (Kraut et al, 1930).

Kallidin liberation (1) by kallikrein and inactivation
in serum (2) as measured by muscle strip constriction
(Werle et al., Biochem Z. 289: 217, 1937)

Ten years later, Eugen Werle (Werle et al., 1937) identified kallikrein as a proteolytic enzyme (‘ferment’) that liberates the biologically highly active, basic polypeptide ‘DK’ or kallidin (i.e lys-bradykinin) from a blood plasma protein called kallidinogen or kininogen (H- and L-kininogen). Hence, kallidin was the first of the basic peptides formed by proteolysis to be identified as a hormone, and later became known as lys-bradykinin, a member of the family of biologically active kinin peptides. Kallidin was first characterized in great detail, especially with regard to its manifold pharmacological effects (Frey et al., 1950). Werle also observed for the first time irreversible ‘fermental degradation’ of kallidin by ‘kininases’ and identified them as peptidases (Werle and Grunz, 1939). Therefore, the fundamental knowledge of the system that we refer to today as the kallikrein-kinin system (cascade) was provided by Frey, Kraut and Werle.

The vital importance of the kallikrein-kinin system for basic mechanisms in biochemistry, patho/physiology, pharmacology and more recently, molecular biology and cell biology, and the great interest and practical benefit of the system to clinical medicine, has stimulated scientists from various disciplines worldwide to become involved in kallikrein-kinin research. Among them are scientists working also on various regulatory or mediator systems that interact with the kallikrein-kinin cascade. In a special highlight issue of Biological Chemistry (Vol. 382, pp. 3-139, 2001) leading experts in their field reviewed relevant topics of major interest, especially regarding (i) the regulation or function of kinin receptors and intracellular signalling events, (ii) the regulatory or therapeutic potential of kinin receptor antagonists in biology, pharmacology and medicine, and (iii) special cellular events associated with the kallikrein-kinin system.

The founder Henning L. Voigt,
his son Jason and his wife Garcia

In view of the present political and economic pressure to produce applicable scientific results in a minimal period of time, it is remarkable to emphasize that only recently, i.e. nearly 70 years after the discovery of the kininases, a drug based on the seminal research following their discovery and designated as angiotensin I converting enzyme (ACE) inhibitor has been shown to be of immense value in the treatment of coronary heart disease (HOPE Study Investigators, 1996; The Heart Outcome Prevention Evaluation Study Investigators, 2000; Results of the HOPE Study Extension, 2005). This drug simultaneously blocks the ACE-catalyzed degradation of kinins and the generation of angiotensin II, two tissue hormones that exhibit opposite biological or pharmacological effects.

A sense of tradition, combined with the concentration of research activities on the kallikrein-kinin system in Munich connected with other notable kinin centres worldwide, kept the memory of the two scientists from the University of Munich, Emil-Karl Frey and Eugen Werle, alive in the scientific community and has led to the establishment of the 'E.K. Frey-E. Werle Foundation of the Henning L. Voigt Family' in 1988.

References

Frey, E.K. (1926): Zusammenhänge zwischen Herzarbeit und Nierentätigkeit. Arch. Klin. Chir. 142, 663 - 669.

Frey, E.K. and Kraut, H. (1926): Über einen von der Niere ausgeschiedenen, die Herztätigkeit anregenden Stoff. Hoppe-Seyler's Z. Physiol. Chem. 157, 32 - 61.

Frey, E.K, Kraut, H. and Werle, E., eds. (1950): Kallikrein-Padutin. F. Enke-Verlag, Stuttgart, Germany.

Kraut, H., Frey, E.K. and Werle, E. (1930): Über die Inaktivierung des Kallikreins. Hoppe-Seyler' s Z. Physiol. Chem. 192, 1 - 21.

Werle, E., Götze, W., Kappler, A. (1937): Über die Wirkung des Kallikreins auf den isolierten Darm und über eine neue darmkontrahierende Substanz. Biochem. Z. 289, 217 - 233.

Werle, E. and Grunz, M. (1939): Zur Kenntnis der darmkontrahierenden, uterus-erregenden und blutdrucksenkenden Substanz DK. Biochem. Z. 301, 429 - 436.

The HOPE Study Investigators (1996): The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Can J. Cardiol. 12, 127-137.

The Heart Outcomes Prevention Evaluation Study Investigators (2000): Vitamin E supplementation and cardiovascular events in high-risk patients. New Engl. J. Med. 342, 154 - 160.

HOPE/HOPE-TOO Study Investigators (2005): Results of the HOPE Study Extension: Long-term effects of ramipril on cardiovascular events and on diabetes. Circulation 112, 1339-1346.