[ACE inhibitors--activators of kinin receptors].

Angiotensin converting enzyme (ACE) inhibitors are widely used for treatment of cardiovascular diseases. The effects of ACE inhibitors on the human bradykinin receptors were investigated. The mode of action of ACE inhibitors is considered. There is evidence that ACE inhibitors exert effects on the vascular system that cannot be attributed simply to the inhibition of ACE activity and accumulation of locally produced bradykinin. ACE inhibitors augment bradykinin effects on receptors indirectly by inducing cross-talk between ACE and the B2 receptor when enzyme and receptor molecules are sterically close, possibly forming a heterodimer. ACE inhibitors activate B1 receptors directly and independently of ACE via the zink-binding consensus sequence HEXXH, which is present in B1, but not in B2 receptor. Particular structure of B2 and B1 are represented, as well as receptor amino acids coupled with the G-proteins. Activation of kinin receptors by ACE inhibitors leads to clinically beneficial effects of ACE inhibitors.

[Structure and physiological significance of angiotensin converting enzyme domains].

Somatic angiotensin converting enzyme (ACE) consists of two homologous catalytic domains (N- and C-domain), each of which bears an active site exhibiting different biochemical properties. The ACE isoforms consisted of one domain were also detected in mammals. Substantial progress in ACE domain research was achieved during the last years, when crystal their structures were determined. The crystal structures of domains in complex with diverse potent ACE inhibitors provided new insights into structure-based differences of the domain active sites. Physiological functions of ACE are not limited by regulation of the cardiovascular system. Recent evidence suggests that the ACE domains may be also involved into control distinct physiological functions. The C-terminal catalytic domain, playing important role in regulation of blood pressure, catalyzes angiotensin I cleavage in vivo. The N-domain contributes to processing of other bioactive peptides for which it exhibits high affinity. Domain-selective inhibitors able to block selectively either the N- or C-domain of ACE have been developed.

[Study of substrate specificity of a new peptide substrate of endothelin converting enzyme].

The new fluorogenic hexapeptide substrate CMC-Ala-Gly-Gly-Trp-Phe-Arg was used as substrate for endothelin-converting enzyme (ECE), angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The specific inhibitors lisinopril (ACE) and thiorphan (NEP) were used for identification of these enzyme activities,

[Angiotensin-converting enzyme and its physiological role]. / Angiotenzin-prevrashchaiushchii ferment, ego fiziologicheskaia rol'.

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.

[Structural and functional characteristics of angiotensin converting enzyme]. / Strukturno-funktsional'nye osobennosti angiotensinprevrashchaiushchego fermenta.

The structure and functions in various tissues of angiotensin converting enzyme (ACE, peptidyl dipeptidase A), a key enzyme in blood pressure regulation, are reviewed. The similarity and differences of two homologous catalytically active N- and C-domains of the ACE molecule are discussed, and different biological functions of these domains are suggested. Natural active single-domain forms of ACE are characterized.

[An endogenous activator of angiotensin-converting enzyme]. / Endogennyi aktivator angiotenzin-prevrashchaiushchego fermenta.

An endogenous activator of the angiotensin-converting enzyme (ACE), unknown earlier, was detected in freshly prepared human neutrophils. Supernatants of the neutrophil suspension produced a 1.6-2-fold activation of the ACE isolated from bovine kidney cortex. The ACE activating effect of these supernatants correlated with concentration of neutrophils in the initial suspension. The activator did not penetrate through membranes of Centricon-30. This activator was also found in blood serum of patients with hereditary deficiency of the complement CI-esterase inhibitor. The neutrophil-released ACE activator is likely to be involved in the modulation of inflammatory responses.

[Participation of serine proteinases in transforming the high molecular weight (600 kDa) form of angiotensin 1-converting enzyme into the low molecular weight form (190 kDa)]. / Uchastie serinovoi proteinazy v prevrashchenii vysokomolekuliarnoi (600 kDa) formy angiotenzin 1-prevrashchaiushchego fermenta v nizkomolekuliarnuiu (190 kDa).

A high molecular form of angiotensin-converting enzyme with mol mass about 600 kDa was found simultaneously with the well-known low molecular enzyme form of 190 kDa after fractionation of freshly prepared extracts from bovine kidney cortex and lung tissues by means of ammonium sulfate or gel filtration on Sephadex G-200. The rate of substrate hydrolysis was adequately Cl'-dependent for both these enzyme forms and specific inhibitors nonapeptide SQ 20881 and pentapeptide SQ 20475 inhibited similarly their activity. The enzyme high molecular form transformed into its low molecular derivative after storage, in freezing-thawing and ultrafiltration. Aprotinin, the inhibitor of serine proteinases, inhibited this kind of transformation. Stable form of the high molecular angiotensin-converting enzyme, which did not transform into its low molecular derivative, was obtained after treatment with agarose-immobilized aprotinin. Endogenous serine proteinases, which may regulate the angiotensin-converting activity in vivo, appears to be responsible for the enzyme transformation into its low molecular derivative.

[Induction of blood plasma carboxycathepsin (angiotensin I-converting enzyme) in normo- and hypertensive rats in response to a single administration of captopril]. / Induktsiia karboksikatepsina (angiotenzin-I-prevrashchaiushchego fermenta) plazmy krovi normo- i gipertenzivnykh krys v otvet na odnokratnoe vvedenie kaptoprila.

The experiments were carried out to elucidate the effect of carboxycathepsin (CC) activity inhibition by a specific inhibitor--captopril--on plasma enzyme concentration in normotensive rats and rats with renovascular hypertension. A single oral administration of captopril (10 mg/kg body weight) produced an increase in CC concentration in both hypertensive and sodium-depleted normotensive rats with a parallel decrease in arterial pressure, but had no effect on sodium-repleted normotensive rats. It is suggested that the increase in plasma CC concentration is a compensatory response to the inhibition of CC activity by captopril; it is also possible that the increase observed reflects the state of renin-angiotensin system.

[Peptides--inhibitors of carboxycathepsin (peptidyl-dipeptidase A) and their role in clinical medicine]. / Peptidy-ingibitory karpoksikatepsina (peptidil-dipeptidazy A) i ikh znachenie dlia klinicheskoi meditsiny.

Properties of the carboxycathepsin inhibitors teprotide, captopryl, enalacryl are considered. Presence of low molecular thermo- and acid stable carboxycathepsin inhibitors of peptide nature in blood serum and lymphocytes is discussed.

[Changes in dipeptidyl carboxypeptidase activity during hypertension and its complications]. / Izmenenie aktivnosti dipeptidil-karboksipeptidazy pri gipertonicheskoi bolezni i ee oslozhneniiakh.

Using the fluorimetric method, the activity of dipeptidyl-carboxypeptidase (DCP) was studied in 85 patients suffering from essential hypertension. It was ascertained that the DCP activity in the blood serum of such patients was significantly higher than in normal subjects. The highest activity of the enzyme was observed in cases where essential hypertension was aggravated by chronic heart failure or an acute impairment of the cerebral circulation. Inflammatory processes in hypertensive patients were associated with a considerable fall in the serum enzyme activity.

[Titration of active centers of enzymes by means of reversible inhibitors. Dipeptidyl-carboxypeptidase - inhibitor SQ 20881 from venom of the snake Bothrops jararca)]. / Titrovanie aktivnykh tsentrov fermentov obratimymi ingibitorami. Dipeptidilkarboksipeptidaza -- ingibitor SQ 20881 iz iada zmei Bothrops jararaca.

The essentials of estimation of the number of enzyme active sites by reversible inhibition are discussed. The necessity of evaluation of the substrate effect on the equilibrium of the systems with a rapidly dissociating enzyme -- inhibitor complex has been demonstrated. Some procedures for determination of the number of active sites of dipeptidyl-carboxypeptidase (EC 3.4.15.1) from bovine kidney cortex, using the competitive inhibitor SQ 20 881 (Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) have been developed. The kinetic and equilibrium constants for the enzyme-inhibitor interaction (ki = 3.2 . 10(6) M-1s-1, k-i = 8 ms-1 and Ki = 2.5 +/- 0.5 nm) have been calculated.

[Isolation and properties of carboxycathepsin (peptidyl-dipeptidase) from bovine lung tissue]. / Vydelenie i svoistva karboksikatepsina (peptidil-dipeptidazy) iz tkani legkikh byka

2200-fold purified homogenous preparation of carboxycathepsin (peptidyl-dipeptidase) is isolated from bovine lung. The enzyme isolated converts angiotensine I into angiotensine II and distroys bradikinin. It is active in neutral medium, is activated by chloride ion and is inhibited by EDTA and Middle Asian snakes venom. The molecular weight of the enzyme is 180 000-190 000 as estimated by means of polyacrylamide gel electrophoresis, its isoelectric point is 4.48-4.53. The comparison of properties and specificity of carboxycathepsin from bovine lung and kidney draws to the conclusion that both enzymes are identical.