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The in vitro cross-effects of inhibitors of renin-angiotensin and fibrinolytic systems on the key enzymes of these systems

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Abstract

The effects of hypotensive agents (captopril, enalaprilat, and lisinopril) on the activities of components of the fibrinolytic system (FS) and the effects of antifibrinolytic agents (6-aminohexanoic acid (6-AHA) and tranexamic acid (t-AMCHA)) on the activities of angiotensin converting enzyme (ACE) were studied in vitro. Enalaprilat did not affect the FS activity. Captopril considerably inhibited the amidase activities of urokinase (u-PA), tissue plasminogen activator (t-PA), and plasmin ([I]50 (2.0−2.6) ± 0.1 mM), and the activation of Glu-plasminogen by t-PA and u-PA ([I]50 (1.50−1.80) ± 0.06 mM), which may be due to the presence of a mercapto group in the inhibitor molecule. Lisinopril did not affect the amidase activities of FS enzymes, but stimulated Glu-plasminogen activation by u-PA and inhibited activation fibrin-bound Glu-plasminogen by t-PA ([I]50 (12.0 ± 0.5) mM). Presumably, these effects can be explained by the presence in lisinopril of a Lys side residue, whose binding to lysine-binding Glu-plasminogen centers resulted, on the one hand, in the transformation from its closed conformation to a semi-open one and, on the other hand, in its desorption from fibrin. Unspecific inhibition of the activity of ACE, a key enzyme of the renin-angiotensin system, in the presence of 6-AHA and t-AMCHA ([I]50 10.0 ± 0.5 and 7.5 ± 0.4 mM, respectively) was found. A decrease in the ACE activity along with the growth of the fibrin monomer concentration was revealed. The data demonstrate that, along with endogenous mediated interaction between FS and RAS, relations based on the direct interactions of exogenous inhibitors of one system affecting the activities of components of another system can take place.

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Abbreviations

ACE:

angiotensin-converting enzyme

6-AHA, AFK-pNA:

INI-Ala-Phe-Lys p-nitroanilide; 6-aminohexanoic acid

t-AMCHA:

trans-(4-aminomethyl)cyclohexanecarboxylic (or tranexamic) acid

FS:

fibrinolytic system

RAS:

renin-angiotensin system

Glu-Pg:

native plasminogen Glu form

LBS:

lysine-binding sites

t-PA:

tissue plasminogen activator

u-PA:

double-stranded urokinase

PAI-1:

type 1 plasminogen activator inhibitor

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Authors and Affiliations

  1. Faculty of Chemistry, Moscow State University, Vorob’evy gory, Moscow, 119992, Russia

    L. I. Mukhametova, P. V. Binevski, R. B. Aisina, O. A. Kost & I. I. Nikolskaya

  2. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, ul. Kosygina 4, Moscow, 117977, Russia

    D. A. Gulin

Authors
  1. L. I. Mukhametova
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  2. D. A. Gulin
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  3. P. V. Binevski
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  4. R. B. Aisina
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  5. O. A. Kost
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  6. I. I. Nikolskaya
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Correspondence to R. B. Aisina.

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Original Russian Text © L.I. Mukhametova, D.A. Gulin, P.V. Binevski, R.B. Aisina, O.A. Kost, I.I. Nikolskaya, 2008, published in Bioorganicheskaya Khimiya, 2008, Vol. 34, No. 4, pp. 471–478.

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Mukhametova, L.I., Gulin, D.A., Binevski, P.V. et al. The in vitro cross-effects of inhibitors of renin-angiotensin and fibrinolytic systems on the key enzymes of these systems. Russ J Bioorg Chem 34, 421–427 (2008). https://doi.org/10.1134/S1068162008040055

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