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At least 19 recordsLinked to original sources
PubMed2000

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides.

The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikrein-kinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikrein-kinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Kinins and kinin receptors in the nervous system.

Kinins, including bradykinin and kallidin, are peptides that are produced and act at the site of tissue injury or inflammation. They induce a variety of effects via the activation of specific B1 or B2 receptors that are coupled to a number of biochemical transduction mechanisms. In the periphery the actions of kinins include vasodilatation, increased vascular permeability and the stimulation of immune cells and peptide-containing sensory neurones to induce pain and a number of neuropeptide-induced reflexes. Mechanisms for kinin synthesis are also present in the CNS where kinins are likely to initiate a similar cascade of events, including an increase in blood flow and plasma leakage. Kinins are potent stimulators of neural and neuroglial tissues to induce the synthesis and release of other pro-inflammatory mediators such as prostanoids and cytotoxins (cytokines, free radicals, nitric oxide). These events lead to neural tissue damage as well as long lasting disturbances in blood-brain barrier function. Animal models for CNS trauma and ischaemia show that increases in kinin activity can be reversed either by kinin receptor antagonists or by the inhibition of kinin production. A number of other central actions have been attributed to kinins including an effect on pain signalling, both within the brain (which may be related to vascular headache) and within the spinal dorsal horn where primary afferent nociceptors can be stimulated. Kinins also appear to play a role in cardiovascular regulation especially during chronic spontaneous hypertension. Presently, however, direct evidence is lacking for the release of kinins in pathophysiological conditions of the CNS and it is not known whether spinal or central neurones, other than afferent nerve terminals, are sensitive to kinins. A more detailed examination of the effects of kinins and their central pharmacology is necessary. It is also important to determine whether the inhibition of kinin activity will alleviate CNS inflammation and whether kinin receptor antagonists are useful in pathological conditions of the CNS.

Amino Acid Sequence↗
PubMed1993

The kinin released from high molecular weight-kininogen is responsible for inflammatory exudation in rats: detection of kinin-free-kininogen in the exudate by immunoblot analysis.

Kinin release and its involvement in inflammatory exudation were assessed by immuno-blot analysis of the kinin-precursor protein, high molecular weight kininogen (HK). HK consists of heavy (H) chain, bradykinin and light (L) chain. After bradykinin was released by plasma kallikrein, HK remains two-chain-kinin-free form;, i.e., H-chain and L-chain link each other through a disulfide bond. By Western blot analysis using antibody recognizing the light chain of HK, a band of 110-kD mass, which corresponds to intact HK, was detected in plasma after SDS-PAGE under reducing conditions, while a 46-kD band, corresponding to the light chain of HK, but no 110-kD band, was found in the exudate of rats with carrageenin-induced pleurisy at 3 hr as well as at 16 h. This result indicates that in the exudate most all of the HK molecules had released kinin to form kinin-free-HK, whereas the HK in the plasma remained intact. On the contrary, low molecular weight kininogen (LK) in the exudate was mostly in its intact form. These results indicate that plasma kallikrein could be activated in the exudate to release kinin from HK, as it reacts exclusively with HK and not with LK, and they are also mostly consistent with the features of the kinin release from the exudate and the plasma. That is, no kinin was detected in the exudate when the latter was incubated with plasma kallikrein, whereas salivary kallikrein did release kinin, indicating that kinin had already been released from HK, but not from LK in the exudate. Immunoblot analysis of HK in the pleural exudate also demonstrated no kinin involvement in phorbol myristate acetate- or zymosan-induced pleurisy, since no light chain band, but an intact HK band, was found in the exudates from these pleurisies.

Animals↗
PubMed1969

PMN-kinin and kinin metabolizing enzymes in normal and malignant leucocytes.

1. Studies have been carried out on the kinin-forming and kinin destroying activity of rabbit macrophages obtained from the lung before and after BCG injection and from the peritoneal cavity following mineral oil injection. A similar study was carried out with L-1210 leukaemic cells obtained from the peritoneal cavity of mice.2. The macrophages and leukaemic cells contain enzymes that form kinins from purified kininogen substrates at acid pH. The kinin-forming activity is not limited to the lysosomal fraction of the cell since it is found in extralysosomal compartments. Delta-guanidovaleryl benzyl ester partially inhibits the kinin-forming activity. Trasylol does not inhibit the kinin-forming activity of these cells, but does inhibit the kininases of these cells. The lack of effectiveness of this agent as a general anti-inflammatory agent is thus explained.3. The kininases of the normal and malignant cells are also inhibited by chloromethyl ketones such as tosyl-lysine chloromethyl ketone (TLCK) and tosyl-phenylalanine-chloromethyl ketone (TPCK) as well as by copper salts. Hydroxyquinoline has no inhibitory action on these cells, indicating that they differ from the plasma kininases.4. Investigation of the kinins produced by enzymes in rabbit and human polymorphonuclear (PMN) cells has demonstrated the formation of a kinin that differs from bradykinin and other known mammalian kinins in its pharmacological properties, molecular weight, and amino-terminal end group. This peptide has been named PMN-kinin.5. Overall, the investigation has demonstrated the importance of white cells in contributing to the formation and destruction of "extra-plasma" sources of kinins by enzymes which differ from plasma enzymes. Anti-inflammatory agents may have different actions on these cell enzymes from those on plasma enzymes.

Animals↗
PubMed1984

Kinin-forming enzyme in rat brain mitochondria fraction and biological activity of a kinin released from rat plasma kininogen by this enzyme.

The kinin-forming enzyme of rat brain was studied by bioassaying kinin using a rat uterus. The enzyme released a kinin from the partially purified kininogen of rat plasma. The activity is exclusively distributed in the mitochondrial fraction and was detected in the pH range of 2.5-4.0 (optimally at pH 3.0). The enzyme was potently inhibited by pepstatin, but not by aprotinin. Released kinin was extracted by n-butanol and it was purified using Amberlite CG-50 absorption and CM-cellulose column chromatography. The elution profile of kinin from the CM-cellulose column did not coincide with that of bradykinin, Lys-bradykinin or Met-Lys-bradykinin. Isolated kinin was inactivated by treatment with chymotrypsin, but not with trypsin. In addition to the contractile activity on rat uterus, the kinin caused contraction of guinea pig ileum, with the response being potentiated by the presence of bradykinin-potentiator B. It also relaxed a rat duodenum, decreased rat blood pressure, and increased the vascular permeability in guinea pigs. Relative potencies of kinin on these pharmacological activities did not coincide with those of bradykinin. From these results, it is concluded that a kinin-forming enzyme is present in the rat brain. It is a cathepsin D-like enzyme, and furthermore, the enzyme releases a kinin-like peptide from the plasma kininogen fraction.

1-Butanol↗
PubMed2000

Kinins and kinin receptors: importance for the activation of leukocytes.

In this article, we analyzed the role of kinins and kinin receptors with respect to the activation of leukocytes. In these cells, the biological effects of kinin peptides are mediated by kinin receptor subtypes B1, B2, or both, depending on species and cell type. In contrast to the other leukocytes, neutrophils contain the complete system for the synthesis and release of bioactive kinins. Consequently, very high concentrations of these peptides can be reached in the close neighborhood of the kinin receptors, in particular at the site of inflammation. Kinins are responsible for many effects in leukocytes including the release of other inflammatory mediators, such as cytokines, prostaglandins, leukotrienes, and reactive oxygen species. Obviously, the potency of kinins to stimulate leukocytes is dependent on the differentiation and especially on the activation stage of these cells. An upregulation of kinin receptors on neutrophils and macrophages appears to be involved in increasing the sensitivity of these cells to kinins at the site of inflammation.

Animals↗
PubMed1982

An improved method for the determination of human blood kinin levels by sensitive kinin radioimmunoassay.

A highly sensitive and specific radioimmunoassay for kinin (minimal detectable amount, 0.5 pg/tube) was applied to measure the blood kinin level. A five ml blood sample was collected with a siliconized needle and plastic syringe which contained 2.5 ml of 0.8 N-HCl. The blood kinin was extracted with butanol, following reextraction with water. According to this procedure, the mean recovery (mean +/- SE) calculated from added 125I-bradykinin (500 CPM) and the known amounts of cold bradykinin were 50.4 +/- 0.8% and 51.1 +/- 2.2%, respectively. In comparison with other sampling methods in 6 normal subjects, the blood samples taken without HCl in syringes showed a higher level (24.4 +/- 10.1 pg/ml) than the samples with HCl (5.3 +/- 1.3 pg/ml). And very high levels were obtained in the plasma samples collected by the method of Talamo or Vinci (0.53 +/- 0.24 ng/ml and 3.5 +/- 1.3 ng/ml, respectively). The kinin content in blood samples taken with HCl was stable at -20 degrees C for at least one month, but increased significantly at room temperature or 4 degrees C for 48 hours. Blood samples were obtained from 17 normal subjects, and 3 patients with acute myocardial infarction. Blood kinin levels in the patient with acute myocardial infarction, 121 +/- 20.9 pg/ml, were significantly higher than those in normal subjects (3.8 +/- 0.5 pg/ml). From these results, it was concluded that high levels of blood kinin reported previously may have resulted from inadequate sampling procedures. Thus, in order to measure blood kinin accurately, inactivation of the kinin generating and destroying enzymes must be done immediately after the sampling. In addition, this radioimmunoassay method should be very useful in investigating the pathophysiological role of blood kinin in various diseases.

Blood Specimen Collection↗
PubMed2004

Activation of the kallikrein-kinin system and release of new kinins through alternative cleavage of kininogens by microbial and human cell proteinases.

Kinins are released from kininogens through the activation of the Hageman factor-prekallikrein system or by tissue kallikrein. These peptides exert various biological activities, such as vascular permeability increase, smooth muscle contraction, pain sensation and induction of hypotension. In many instances kinins are thought to be involved in the pathophysiology of various diseases. Recent studies have revealed that microbial and human cell proteinases activate Hageman factor and/or prekallikrein, or directly release kinin from kininogens. This review discusses the activation of the kinin-release system by mast-cell tryptase and microbial proteinases, including gingipains, which are cysteine proteinases from Porphyromonas gingivalis , the major pathogen of periodontal disease. Each enzyme is evaluated in the context of its association to allergy and infectious diseases, respectively. Furthermore, a novel system of kinin generation directly from kininogens by the concerted action of two proteinases is described. An interesting example of this system with implications to bacterial pathogenicity is the release of kinins from kininogens by neutrophil elastase and a synergistic action of cysteine proteinases from Staphylococcus aureus . This alternative production of kinins by proteinases present in diseased sites indicates a significant contribution of proteinases other than kallikreins in kinin generation. Therefore kinin receptor antagonists and proteinase inhibitors may be useful as therapeutic agents.

Bacterial Physiological Phenomena↗
PubMed1984

The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue.

Vasogenic edema was induced in mongrel cats by cold injury to study uptake and activation of the plasma-kallikrein-kinin system in central nervous system (CNS) tissue. A method was developed for quantitative assessment of kinin formation in affected brain tissue areas. Gross disruption of the blood-brain barrier by focal trauma causes marked penetration of plasma kininogens into necrotic and edematous brain tissue. Moreover, the kallikrein-kinin (KK) system was activated in both necrotic and perifocal edematous areas, and was markedly enhanced by additional cerebral ischemia. Formation of kinins in necrotic brain tissue led to consumption of approximately 60% to 80% of the amount of kininogens being taken up. In perifocal edematous tissue, formation of kinins was less pronounced, or even absent. However, if cerebral ischemia evolved after severe intracranial hypertension, kinins were also formed in the perifocal edematous brain. The intravascular origin of kininogens found in pathological tissue areas secondary to injury was deduced from the observation that cerebral tissue of the contralateral hemisphere with an intact blood-brain barrier had no measurable quantities of kininogens. Consumption of plasma kininogens or formation of kinins were assessed as the difference of the total amount of plasma kininogens taken up into the tissue minus the amount of kininogens found in the brain at postmortem examination. The data indicate that uptake and activation of the plasma-KK system might occur under all pathological conditions in which blood-brain barrier damage permits cerebral penetration of plasma proteins, such as with cerebral contusion, focal ischemia, and tumors. The potent pathophysiological mechanisms induced by kinins in CNS tissue, such as formation of brain edema, microcirculatory dysfunction, and enhancement of blood-brain barrier permeability, together with their formation in focal and perifocal pathological brain tissue, provide further support for a mediator function of the KK system. Methods that specifically interfere with the formation of kinins in damaged brain should therefore be expected to attenuate vasogenic edema.

Animals↗
PubMed1986

Renal vasoconstrictive effect of kinins mediated by B1-kinin receptors.

The nature of the renal vascular actions of kinins, their dependence on prostaglandins and B1-kinin receptor responses were studied in functioning isolated perfused rat kidneys (IK). Lysylbradykinin (LBK), 0.28 and 0.7 microM, transiently decreased and then markedly increased the renal vascular resistance (RVR) in a sustained manner. Bradykinin (BK) at the same doses also had a transient vasorelaxant but not a sustained vasoconstrictive effect. The inactivation of LBK and BK by the IK did not account for the transient nature of their vasorelaxant effect. Indomethacin (5 microM) markedly blunted LBK-induced decrease but not increase in RVR. The B1-kinin receptor agonist desArg9-BK (0.4-1.0 microM) did not decrease RVR but, as LBK, markedly increased RVR in a dose-related manner. The B1-kinin receptor antagonist [Leu8]desArg9-BK had no effect on its own but inhibited the desArg9-BK-induced vasoconstriction in a stoichiometric manner. This antagonist at 4.0 microM also completely abolished the vasoconstrictive effect of 0.7 microM LBK, whereas it potentiated and prolonged its vasorelaxant effect. The results demonstrate that kinins, particularly LBK, have bimodal effects on the renal vascular resistance of the isolated perfused rat kidney. The vasorelaxant effect is at least partly mediated by prostaglandins whereas the vasoconstrictive effect of LBK and/or its renal metabolites has the typical character of a B1-kinin receptor response. It is postulated that B1-kinin receptor responses may be of importance in the generation and/or maintenance of renal vasoconstriction in disease states which lead to renal failure.

Animals↗
PubMed1989

A novel kinin, Met-Ile-Ser-bradykinin (Met-T-kinin) is released from T-kininogen by an acid proteinase of granulomatous tissues in rats.

Acid proteinase of granulomatous tissues in rats with carrageenin-induced inflammation released two types of kinin from T-kininogen. The kinin was identified as Ile-Ser-bradykinin (T-kinin) and a novel kinin, Met-Ile-Ser-bradykinin (Met-T-kinin), from determination of its amino acid composition and its immunoreactivity toward anti-bradykinin antiserum. The release of T-kinin and Met-T-kinin from T-kininogen were found to occur by consecutive cleavage by cathepsin D and 72 kDa protease.

Amino Acids↗
PubMed1988

Identification of T-kinin-Leu(T-kinin-containing peptide) released from T-kininogen by cathepsin D of granulomatous tissues in rats.

Acid proteinases of granulomatous tissues in rats with carrageenin-induced inflammation released kinin from T-kininogen. By column chromatography on pepstatin-Sepharose 4B, two types of acid proteinase seems to be responsible for kinin release. One of the acid proteinase was identified as cathepsin D from SDS-polyacrylamide gel electrophoresis and Western-blot analysis, using anti-rat liver cathepsin D IgG. Cathepsin D alone could not release T-kinin, but T-kinin-containing peptides. The T-kinin-containing peptides were separated into two peptides by reverse-phase high-performance liquid chromatography. From determination of its amino acid composition and its immunoreactivity toward anti-bradykinin antiserum, one of the T-kinin-containing peptides was identified as T-kinin-Leu.

Amino Acids↗
PubMed1996

Translocation of the neutrophil kinin moiety and changes in the regulation of kinin receptors in inflammation.

A molecular response to cell injury is the formation of chemotactic mediators that attract neutrophils to sites of inflammation. The question whether neutrophils contribute to circulating levels of kinins was examined in infections and inflammatory disorders. This novel hypothesis was tested using circulating neutrophils harvested from patients with tuberculosis meningitis and pneumonia. These neutrophils showed a distinct loss of only the kinin moiety from the kininogen located on the external surface. A similar loss of the kinin peptide was observed on the synovial fluid neutrophils obtained from the swollen, inflamed joints of patients with rheumatoid arthritis. The intriguing question is whether the circulating neutrophils simply reflect those cells re-entering the circulation from sites of inflammation. Anti-peptide antibodies to the peptide loops of cloned B1 and B2 receptors have provided a powerful probe for the cellular identification of the two kinin receptor families. We report the first localisation of B1 receptors on the basement membranes of bronchopulmonary cells and the surrounding fibrous stroma in transbronchial biopsies taken from patients with interstitial lung disease associated with progressive systemic sclerosis. Although binding of labelled bradykinin to neuronal membranes has been demonstrated, this is the first conclusive evidence for the presence of B1 kinin receptors in the neurons of human hypothalamus, caudate nucleus and the substancia gelatinosa of the spinal cord. Mapping of the B2 receptors in human tissues shows upregulation on the neutrophils gathered from inflamed joints, and absence from cell membranes of acutely rejecting transplant kidney. In addition, B2 receptors have also been demonstrated in neurons of the brain hypothalamus, caudate nucleus and cerebral cortex. Kinin receptor localisations in human tissue has considerable therapeutic implications.

Brain↗
PubMed2002

The use of kinin B1 and B2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level.

The mechanisms by which kinins induce hyperalgesia in the spinal cord were investigated by using B(1) or B(2) knockout mice in conjunction with kinin selective agonists and antagonists. The i.t. administration of the kinin B(2) receptor agonists, bradykinin (BK) or Tyr(8)-BK produced dose-related thermal hyperalgesia evaluated in the hot-plate test. BK-induced hyperalgesia was abolished by the B(2) receptor antagonist Hoe 140. The i.t. injection of the kinin B(1) receptor agonists, des-Arg(9)-bradykinin (DABK) or des-Arg(10)-kallidin (DAKD) also caused dose-related thermal hyperalgesia. Different from the B(2) agonists, the i.t. injection of DABK or DAKD caused a weak, but prolonged hyperalgesia, an effect that was blocked by the B(1) receptor antagonist des-Arg(9)-[Leu(8)]-bradykinin (DALBK). The i.t. injection of BK caused thermal hyperalgesia in wild-type mice (WT) and in the B(1) receptor knockout mice (B(1)R KO), but not in the B(2) receptor knockout mice (B(2)R KO). Similarly, the i.t. injection of DABK elicited thermal hyperalgesia in WT mice, but not in B(1)R KO mice. However, DABK-induced hyperalgesia was more pronounced in the B(2)R KO mice when compared with the WT mice. The i.t. injection of Hoe 140 or DALBK inhibited the second phase of formalin (F)-induced nociception. Furthermore, i.t. Hoe 140, but not DALBK, also inhibits the first phase of F response. Finally, the i.t. injection of DALBK, but not of Hoe 140, inhibits the long-term thermal hyperalgesia observed in the ipsilateral and in contralateral paws after intraplantar injection with complete Freund's adjuvant. These findings provide evidence that kinins acting at both B(1) and B(2) receptors at the spinal level exert a critical role in controlling the nociceptive processing mechanisms. Therefore, selective kinin antagonists against both receptors are of potential interest drugs to treat some pain states.

Animals↗
PubMedDate not supplied

[Kinin system components, free kinins and proteinase inhibitors in the edematous fluids of nephrotic syndrome patients].

Main components of the kinin system, free kinins, total arginine esterase activity content of alpha 1-antitrypsin and alpha 2-macroglobulin fractions were estimated in various edematous fluids (transduates of different localization, pleural exudates of the inflammatory type) of patients with nephrotic syndrome of various etiology. Noninflammatory edematous fluids (interstitial, abdominal and pleural transudates) were found to contain activated kallikrein and prekallikrein from blood plasma; 3-10 ng/ml of free kinins were present in interstitial edematous fluids and 30-60 ng/ml - in abdominal transudate. Kinins of abdominal transudate were identified with bradikinin by chromatographic properties; a single low-molecular form of kininogene was found, its content did not exceed 10% of the substance occurring in blood plasma of the patients. These edematous fluids practically did not exhibit the kininase activity and contained unsignificant amounts of proteinase inhibitors. Pleural exdates of the inflammatory type were distinctly different from transudates in content of the kinin system components. Depending on the higher content of protein (2.5% as compared with 0.3-0.7% in transudates) the exudates contained high-molecular kininogene and kininase I. Relative content of kallikrein in pleural exudates was lower and that of prekallikrein - higher as compared with transudates; acid kininogenases were not observed. Free kinins (30 ng/ml) were found in three samples of pleural exudates out of five samples studied. The inflammatory type of pleural exudates correlated with the high level of alpha 1-antitrypsin. As shown by comparative analysis of protein fractions from edematous fluids and corresponding samples of blood plasma of patients with nephrotic syndrome, diffusion is the main reason, which determines the course of protein transition from inter-into exovasal space, under conditions of increased vascular permeability. Kallikrein activation and extravasal formation of bradikinin were apparently the long-term affecting factors, supporting the state of increased vascular permeability in nephrotic syndrome; they had an aggravating role in pathogenesis of refractory nephrotic edema, nephrotic crises and cutaneous erythema.

Adolescent↗