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The kallikrein-kinin system (KKS) is the key proteolytic system participating in control of a wide spectrum of physiological functions and the development of many pathological conditions. This explains great interest in structures, functions and molecular biology of separate components of the system, molecular mechanisms of their interaction and relationship with other regulatory systems. The information in this field for the last two decades clarifies the role of KKS in morphogenesis of cells, regulation of smooth muscular contractility of some organs, decrease of blood pressure, increase of vascular permeability, the development of inflammation, transformation of cells and the other functions of both physiological and pathological processes. Essential progress in understanding of functions KKS was made by the discovery and study of bradykinin receptors, cloning of kininogen and kallikrein encoding genes, revealing of domain structure of kininogen, prekallikrein and some kininase and decoding of mechanisms of contact phase of proteolytic system activation in blood plasma.

Angiotensin-converting enzyme (ACE, peptidyl dipeptidase A) is well known as a key enzyme involved in regulation of blood pressure. Regulation of blood pressure is the main but not the only ACE function. This enzyme is also involved in the regulation of a range of other physiological processes including control of cells proliferation. Particular role of the enzyme in a given process is determined by its localization and its action on regulatory peptides. Structural peculiarities of angiotensin-converting enzyme and its gene polymorphism related to its physiological function are discussed. ACE molecule consists of two large homologous domains (N- and C-domains), differing in their catalytical properties. These differences are suggested to be physiologically important. Endogenous substrates specific for each of these domains and natural active single-domain ACE forms were revealed. An association between the ACE gene polymorphism and plasma ACE levels, as well as with an increased risk of various cardiovascular and renal diseases was observed.

It is commonly accepted that the tolerance to insulin and hyperglycemia of the patients with non-insulin dependent diabetes mellitus (NIDDM) is due to some defect of insulin receptors or disturbances in the signaling pathway of the cell. This disease is often accompanied by hypertension. In this paper the high activity of plasma kallikrein-kinin system (KKS) (kallikrein activity was 6-8 times higher than normal), of angiotensin-converting enzyme (ACE) (4 times greater than normal), and of leukocyte elastase (2.7 times higher than normal) were demonstrated in plasma of patients with NIDDM. Increasing of KKS activity was coincident with rising of ACE activity, which may be the cause of the fast bradykinin inactivation and arising of hypertension. The treatment with ACE inhibitor during 3 months (4 mg of Perindopril per day) decreased ACE activity in patients' plasma which was accompanied with decreasing of the arterial pressure and some restoration of the carbohydrate metabolism indicators. The hyperinsulinemic euglycaemic clamping of 7 patients with NIDDM and essential hypertension showed that ACE-inhibitor (Perindopril, 4 mg) prevented bradykinin from destruction and increased the glucose consumption by tissues. The high activity of polymorphonuclear leukocytes and secretion of the elastase in NIDDM patients' plasma and/or instability of plasmatic and granular membranes of leukocyte in conditions of hyperglycaemic plasma are probably the cause of endothelial irritation and high ACE secretion. Secondly, the leukocyte may be the cause of injuring and decreasing of susceptibility of the cell receptors for insulin and bradykinin.

Some parameters of the kallikrein-kinin system and the antiproteinase potential were studied in patients with diffuse peritonitis during the routine treatment course, after additional intramuscular administration of mexidol (inhibitor of free radical oxidation with antiproteinase activity) as well as after treatment of the patients with physiological solution containing ozone (4-7 mg/l used as a donor of free radicals), which was applied for washing of abdominal cavity in one group of patients during surgical operation and for intravenous administration in the other group. The kallikreinkinin system parameters were distinctly altered in the patients with peritonitis and the rate of the system activation correlated with the disease severity. Content of the alpha 1-inhibitor of proteinases (alpha 1-PI) was increased by the middle period of the treatment course and decreased as the inflammation lowered. alpha 2-Macroglobulin (alpha 2-MG) was altered less distinctly as compared with alpha 1-PI. Patterns of the antiproteinase potential in blood plasma (alpha 1-PI and alpha 2-MG) may be used for diagnostic and prognostic purposes in post-surgical treatment of patients with diffuse peritonitis; a decrease in the potential value proved to be a symptom of danger. Both mexidole and ozone exhibited positive clinical effect in treatment of the disease. Although these drugs had an opposing effect on the proteinases activity, their similar action on the antiproteinase potential appears to be responsible for the medicinal efficiency. Clinical effect of the drugs may be arranged as follows: mexidole, ozone administered intravenously and ozone used for intraabdominal washing.

Activity of the kallikrein-kinin system and proteinase inhibitors were studied in blood plasma of children at various stages of tubulointerstitial nephritis, pyelonephritis and dysmetabolic nephropathy. Similar alterations in the activities of kallikrein-kinin system and in the rate of proteolysis inhibition were observed in tubulointerstitial nephritis and pyelonephritis. Supplementary demonstrations were obtained about development of inflammation in tubulointerstitial nephritis. Absence of the kallikrein-kinin system activation and a decrease in the alpha 2-macroglobulin content were detected in dysmetabolic nephropathy. Definite components of the kallikrein-kinin system and the proteolysis inhibitors may be used as indicators in differential diagnosis of tubulointerstitial nephritis and dysmetabolic nephropathy.

Content of components of the kallikrein-kinin system was studied in the plasma of rats treated with low frequency acoustic signals. Low frequency acoustic treatment caused an increase in the rate of kallikrein formation from its inactive precursor prekallikrein, whose content was decreased; antiprotease activity was increased in the plasma mainly due to activation of alpha 1-antitrypsin. At the same time, activation of the kallikrein-kinin system led to a compensatory increase in the activity of kininase. The findings suggest that the kallikrein-kinin system is involved in the formation of the body's responses in the low-frequency accoustic field.

Activation of the kallikrein-kinin system was detected in chronic renal failure treated by routine therapy. In blood plasma of the patients with chronic renal failure, kallikrein was activated from 34.2 to 63.2 mU/ml, while activity of prekallikrein was decreased from 382.0 to 117.8 mU/ml; BAEE-esterase and elastase-like activities simultaneously increased from 340 +/- 20 to 464 +/- 43 mU/ml and from 150 +/- 20 to 340 +/- 18 mU/ml, respectively. In the patients on hemodialysis during the interdialysis period, there were reductions of BAEE-esterase and kallikrein activities to 265.8 +/- 18.5 and 25.9 mI/ml, respectively; and the content of prekallikrein remained decreased. During hemodialysis the elastase-like activity was markedly increased up to 501 mU/ml due to leukocyte activation. The findings suggest that during hemodialysis, due to leukocytic elastase, there is a possible occurrence of thromboses as a result of a potential depletion of the kallikrein-kinin system and decreased blood antiproteolytic potential, including antithrombin III.

A state of the kallikrein-kinin system, activity of proteolysis inhibitors were studied simultaneously with the functional activity of neutrophils and content of lysozyme in blood serum of 21 patients with chronic kidney insufficiency. Two types of alterations in the kallikrein-kinin system were found in 13 patients maintained on hemodialysis: in four patients content of kallikrein was increased 8-fold as compared with normal level with a decrease in content of prekallikrein, while in nine patients activity of kallikrein was similar to control values but content of prekallikrein was still further decreased. Content of alpha 1-proteinase inhibitor (PI) was distinctly decreased (2-2.5-fold) in these patients, however, the decrease of the inhibitor was not observed in four patients; activity of alpha 2-macroglobulin tended to decrease. The ratio of active neutrophils and content of lysozyme were increased in blood serum of the majority of the patients. Hemodialysis, activation of the kallikrein-kinin system and stimulation of neutrophils appear to be responsible for a decrease in PI activity. The decrease in the PI activity and stimulation of the kallikrein-kinin system suggest that impairments in regulation of proteolysis could be corrected by means of exogenous proteinase inhibitors. In crisis of allogenic kidney rejection activities of PI and prekallikrein were decreased. Drastic, uneven alterations of the patterns studied were detected in pyo-inflammatory complications not related to the rejection crisis.