Dextran sulfate activates contact system and mediates arterial hypotension via B2 kinin receptors
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Abstract:
To define some of the mechanisms underlying dextran sulfate (DXS)-induced hypotension, we investigated the effects of either the plasma kallikrein inhibitor des-Pro2-[Arg15] aprotinin (BAY x 4620) or the specific bradykinin B2-receptor antagonist Hoe-140 on the hypotensive response to DXS. In the first study, anesthetized miniature pigs were given DXS alone, DXS plus BAY x 4620 in various doses, or saline. As expected, DXS alone produced a profound but transient systemic arterial hypotension with a concomitant reduction in kininogen. Circulating kinin levels, complement fragment des-Arg-C3a, and fibrin monomer were all increased. Treatment with BAY x 4620 produced a dose-dependent attenuation of these effects with complete blockade of the hypotension as well as the observed biochemical changes at the highest dose (360 mg). In a second study, two groups of pigs were given either DXS alone or DXS plus Hoe-140. DXS-induced hypotension was completely blocked by Hoe-140 pretreatment; however, kininogen was again depleted. We conclude, therefore, that DXS-induced hypotension is produced by activation of plasma kallikrein that results in the production of bradykinin and that liberation of bradykinin and its action on B2 receptors in the vasculature are both necessary and sufficient to produce the observed effects on circulatory pressure.Keywords:
Prekallikrein
Aprotinin
Prekallikrein
High-molecular-weight kininogen
Factor XII
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The influence of the hyaluronanbinding protease (PHBSP), a plasma enzyme with FVII and prourokinase activating potency, on components of the contact phase (kallikrein/kinin) system was investigated. No activation or cleavage of the proenzymes involved in the contact phase system was observed. The procofactor high molecular weight kininogen (HK), however, was cleaved in vitro by PHBSP in the absence of any charged surface, releasing the activated cofactor and the vasoactive nonapeptide bradykinin. Glycosoaminoglycans strongly enhanced the reaction. The cleavage was comparable to that of plasma kallikrein, but clearly different from that of coagulation factor FXIa. Upon extended incubation with PHBSP, the light chain was further processed, partially removing about 60 amino acid residues from the Nterminus of domain D5 of the light chain. These cleavage site(s) were distinct from plasma kallikrein or FXIa cleavage sites. PHBSP and, more interestingly, also plasma kallikrein could cleave low molecular weight kininogen in vitro, indicating that domains D5H and D6H are no prerequisite for kininogen cleavage. PHBSP was also able to release bradykinin from HK in plasma where the procofactor circulates predominantly in complex with plasma kallikrein or FXI. In conclusion, PHBSP represents a novel kininogencleaving and bradykininreleasing enzyme in plasma that shares significant catalytic similarities with plasma kallikrein. Since they are structurally unrelated in their heavy chains (propeptide), their similar in vivo catalytic activities might be directed at distinct sites where PHBSP could induce processes that are related to the kallikrein/kinin system.
Prekallikrein
High-molecular-weight kininogen
Cleavage (geology)
Factor XII
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Prekallikrein
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Prekallikrein
High-molecular-weight kininogen
Factor XII
Cationic polymerization
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Methods were developed for determining the kininogen fractions, kininase and prekallikrein. The plasma prekallikrein was activated by 20 % (v/v) acetone for about 17 hours (20–24°). Urine kallikrein was prepared by dialysis of urine against running tap water for about 24 hours. Kininase activity was eliminated in plasma, plasma kallikrein and urine kallikrein by incubation at 37° with EDTA‐2Na (1.0 × 10 2 M) for about 24 hours. Kinin assays were carried out on the isolated rat uterus. Released kinin was calculated as μg bradykinin/ml plasma. The total kininogen, whether determined by activation with acetone (16 % v/v for not less than 5 hours) and subsequent incubation with plasma kallikrein, by incubation with plasma kallikrein and then urine kallikrein, or by incubation with acetone (20 % v/v for 17 hours) and subsequent evaporation of the acetone, was found to be the same, 2.0 μg/ml plasma as an average value of 7 plasma batches corresponding to a total of 90 rats (S. D. = 0.09). The average values of kinin released by incubation with plasma kallikrein and by urine kallikrein were 1.5 μg/ml and 1.4 μg/ml plasma respectively with S. D. values of 0.11 and 0.06 respectively. The procedures for kininase and for prekallikrein determinations corresponded closely to previously published methods for estimation of the same parameters in human plasma ( RINVIK, DYRUD & BRISEID 1966 ; BRISEID, DYRUD & ARNTZEN 1968 ).
Prekallikrein
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Indirect evidence has been provided for the presence of 3 kininogen fractions: The average amounts of kinin released by rat plasma kallikrein (1.5 μg/ml plasma, S. E. M. = 0.03) and by rat urine kallikrein (1.4 μg/ml plasma, S. E. M. = 0.03) in 7 plasma batches corresponding to a total of 90 rats, when added up, significantly exceeded the total kininogen (2.0 μg/ml plasma, S. E. M. = 0.04). Methods and materials were as described by BRISEID, DYRUD & ÖIE (1970). It is suggested that plasma kallikrein released kinin from 2 kininogen fractions, S1″ and S1″, and that urine kallikrein released kinin from 2 kininogen fractions, S1″ and S2. Repeated incubation with each of the kininogenase preparations used did not increase the yield of kinin. Soybean trypsin inhibitor did not reduce the amount of kinin released by urine kallikrein; the plasma kallikrein, however, was strongly inhibited. In control experiments leucine aminopeptidase transformed kallidin to bradykinin, but did not increase the kinin activity of the urine kallikrein incubates.
Kallidin
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1. The plasma of non-pregnant women contains practically no kinins and only traces of kallikrein. Treatment of the plasma with kaolin produces additional amounts of kallikrein from prekallikrein and of kinin from kininogen. 2. During the second stage of labour, plasma kallikrein is increased and the amount of kallikrein inhibitors is decreased. The plasma kinin-forming activity is only slightly increased due, apparently, to a fall in plasma kininogen. 3. Plasma kallikrein causes a rise in the contractile tonus of the isolated rat and human myometrium.
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SUMMARY Release of vasodilator peptides (collectively known as “plasma kinin”) from human plasma was measured using synthetic bradykinin as a reference standard. Under optimal conditions an equivalent of 3–4 μg, of bradykinin/ml. of plasma can be recovered. As the kinin is liberated its precursor (kininogen) is quantitatively exhausted. Trypsin and glandular kallikreins (as in saliva or urine) release the maximal amount of kinin and consume all of the precursor. In this they differ from plasma kallikrein whose activation is initiated by contact with foreign surfaces, organic solvents, and acidification, These “intrinsic” mechanisms are dependent on the presence of Hageman factor (also required for blood clotting) and “component A”, which can be identified with plasma kallikreinogen. Activated component A (i.e. plasma kallikrein) releases 1–1.5 μg. of kinin/ml. in a rapid reaction with approximately one‐third of kininogen. It is suggested that this is the precursor of nonapeptide only and corresponds to “component B”. In the other 2/3 of kininogen the kinin is bound as a decapeptide which can either be released as such (by glandular kallikreins) or serve as another source of the nonapeptide (with trypsin). The affinity of plasma kallikrein for this substrate is very low.
Factor XII
Prekallikrein
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High-molecular-weight kininogen
Prekallikrein
Factor XII
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We studied contact factors and kinin-kallikrein in normal non-pregnant and pregnant women, FXII deficient toxemia and DIC. The results obtained are as follows: 1. The levels of plasma prekallikrein, high molecular weight kininogen, kallikrein inhibitor, and C-1 INA were gradually decreased at delivery, and the levels of kallikrein like activity and bradykinin were increased during pregnancy and at the time of parturition. These facts indicate that kinin kallikrein systems played important role in uterine contraction. 2. The levels of contact factors (FXII and FXI) were lower at delivery than those of term. 3. In rat uterus, specific binding of bradykinin was observed by the method of radio receptor assay in the pelet of 10,000 X g fetal membranes, and its activity was 38%. 4. A synthetic kallikrein inhibitor (OS-291, MS) and bradykinin antagonist inhibited completely spontaneous uterine contraction of Wistar rats during delivery. 5. In the case of FXII deficiency, the levels of plasma prekallikrein, high molecular weight kininogen were normal, but at delivery, these levels were lower than those of term. The levels of kallikrein like activity which was half of normal parturition level was increased at parturition. 6. In cases of DIC (17) and severe toxemia (22), plasma prekallikrein levels were lower than the normal controls. The decrease was due to consumption of plasma prekallikrein to kallikrein activation.
Prekallikrein
Factor XII
High-molecular-weight kininogen
Aprotinin
Uterine contraction
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