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Randal A Skidgel - One of the best experts on this subject based on the ideXlab platform.
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Kininase i type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin b1 receptor agonists
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Sakonwun Sangsree, Richard D Minshall, Viktor Brovkovych, Randal A SkidgelAbstract:Kininase I-type carboxypeptidases convert native kinin agonists for B2 receptors into B1 receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carbo...
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Kininase i type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin b1 receptor agonists regulation of cardiovascular signaling by kinins and products of similar converting enzyme systems
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Sakonwun Sangsree, Richard D Minshall, Viktor Brovkovych, Randal A SkidgelAbstract:Kininase I-type carboxypeptidases convert native kinin agonists for B 2 receptors into B 1 receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carboxypeptidase M (CPM) and carboxypeptidase D (CPD) make them ideally situated to regulate kinin activity. Nitric oxide (NO) release from human lung microvascular endothelial cells (HLMVEC) was measured directly in real time with a porphyrinic microsensor. Bradykinin (1-100 nM) elicited a transient (5 min) peak of generation of NO that was blocked by the B 2 antagonist HOE 140, whereas B 1 agonist des-Arg 10 -kallidin caused a small linear increase in NO over 20 min. Treatment of HLMVEC with 5 ng/ml interleukin-1β and 200 U/ml interferon-γ for 16 h upregulated B 1 receptors as shown by an approximately fourfold increase in prolonged (>20 min) output of NO in response to des-Arg 10 -kallidin, which was blocked by the B 1 antagonist des-Arg 10 -Leu 9 -kallidin. B 2 receptor agonists bradykinin or kallidin also generated prolonged NO production in treated HLMVEC, which was significantly reduced by either a B 1 antagonist or carboxypeptidase inhibitor, and completely abolished with a combination of B 1 and B 2 receptor antagonists. Furthermore, CPM and CPD activities were increased about twofold in membrane fractions of HLMVEC treated with interleukin-1β and interferon-γ compared with control cells. Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the cell membrane. These data show that cellular Kininase I-type carboxypeptidases can enhance kinin signaling and NO production by converting B 2 agonists to B 1 agonists, especially in inflammatory conditions.
Albert Adam - One of the best experts on this subject based on the ideXlab platform.
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serum interspecies differences in metabolic pathways of bradykinin and des arg9 bk influence of enalaprilat
American Journal of Physiology-heart and Circulatory Physiology, 1996Co-Authors: Anick Décarie, Réjean Couture, Philippe Raymond, Nicole Gervais, Albert AdamAbstract:Among the different enzymes responsible for the metabolism of bradykinin (BK), three peptidases look relevant in vivo: Kininase I (KI), which transforms BK into its active metabolite, [des-Arg9]BK; Kininase II (KII); and neutral endopeptidase, which inactivate BK and [des-Arg9]BK. The in vitro incubation of BK and [des-Arg9]BK in the serum of four species with or without enalaprilat and the quantification of the immunoreactivity of both peptides at different time intervals allowed the measurement of the kinetic parameters characterizing their metabolic pathways. Highly sensitive chemiluminescent enzyme immunoassays were used to measure the residual concentrations of BK and [des-Arg9]BK. Half-life (t1/2) of BK showed significant difference among species: rats (10 +/- 1 s) = dogs (13 +/- 1 s) dogs (50.0 +/- 3.9%). Its importance in the hydrolysis of [des-Arg9]BK was 5.2 +/- 0.5% in rats > humans (3.4 +/- 1.2%) = rabbits (1.8 +/- 0.2%) = rats (1.4 +/- 0.3%). Finally, no significant difference on t1/2 values for BK and [des-Arg9]BK could be demonstrated between serum and plasma treated with either sodium citrate or a thrombin inhibitor. These results revealed striking species differences in the serum metabolism of kinins that could address at least partially some of the controversial data related to the cardioprotective role of kinins.
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effect of enalaprilat on bradykinin and des arg9 bradykinin release following reperfusion of the ischaemic rat heart
British Journal of Pharmacology, 1995Co-Authors: Daniel Lamontagne, R Nadeau, Albert AdamAbstract:1. The release of bradykinin (BK) and its metabolite, des-Arg9-bradykinin (des-Arg9-BK), was studied following reperfusion of a globally ischaemic rat heart. 2. BK-like immunoreactivity increased from 13 +/- 3 (preischaemic value) to 48 +/- 12 fmol min-1 g-1 (P < 0.05, n = 14) 30 s after reperfusion. No difference in BK release was found between control hearts and hearts pretreated with the angiotensin converting enzyme (ACE or Kininase II) inhibitor, enalaprilat (50 ng ml-1). 3. No significant change in des-Arg9-BK-like immunoreactivity during reperfusion was observed in control hearts. In contrast, des-Arg9-BK-like immunoreactivity rose from 44 +/- 15 to 177 +/- 61 fmol min-1 g-1 (P < 0.05, n = 7) 30 s after reperfusion in enalaprilat-treated hearts. 4. In conclusion, BK is released upon reperfusion of the globally ischaemic rat heart. ACE inhibitors, through the inhibition of Kininase II, increase the formation of the active metabolite, des-Arg9-BK.
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Development of digoxigenin-labeled peptide: Application to chemiluminoenzyme immunoassay of bradykinin in inflamed tissues
Peptides, 1994Co-Authors: Anick Décarie, Réjean Couture, Jean Closset, Guy Drapeau, Albert AdamAbstract:Abstract A new ultrasensitive chemiluminoenzyme immunoassay (CLEIA) using digoxigenin-labeled bradykinin (BK) as a tracer is proposed to quantify kinins in tissue samples. Rabbit polyclonal IgGs anti-BK directed against the C- terminal end were used for the immunoconcentration step along with dioxetane derivative for the revelation step. The sensitivity of the assay for BK was 0.1 fmol/ml with ED 50 of 0.78 pmol/ml. This method was applied on extracts of normal and carrageenan-inflamed tissues. The edema produced by the injection of carrageenan in rat hindpaws was associated with a sevenfold increase of immunoreactive kinins in the inflamed paw extract ( from 0.021 ± 0.007 to 0.141 ± 0.021 pmol/g tissue ; p ), the immunoreactivity corresponded to BK, kallidin, and T-kinin after HPLC separation. When a mixture of inhibitors of Kininase I (mergepta) and Kininase II (captopril) was coinjected with carrageenan, the carrageenan-induced edema was unaffected but the kinin tissue content was significantly enhanced ( 0.207 ± 0.003 pmol/g tissue ; p ). However, the kinin tissue content and the edema response were unaltered by inhibitors given separately. Hence, this highly sensitive assay provides a biochemical evidence that kinins may act as proinflammatory mediators, and highlights a compensatory increase of Kininase I and II activities in inflamed tissues.
Richard D Minshall - One of the best experts on this subject based on the ideXlab platform.
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Kininase i type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin b1 receptor agonists
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Sakonwun Sangsree, Richard D Minshall, Viktor Brovkovych, Randal A SkidgelAbstract:Kininase I-type carboxypeptidases convert native kinin agonists for B2 receptors into B1 receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carbo...
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Kininase i type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin b1 receptor agonists regulation of cardiovascular signaling by kinins and products of similar converting enzyme systems
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Sakonwun Sangsree, Richard D Minshall, Viktor Brovkovych, Randal A SkidgelAbstract:Kininase I-type carboxypeptidases convert native kinin agonists for B 2 receptors into B 1 receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carboxypeptidase M (CPM) and carboxypeptidase D (CPD) make them ideally situated to regulate kinin activity. Nitric oxide (NO) release from human lung microvascular endothelial cells (HLMVEC) was measured directly in real time with a porphyrinic microsensor. Bradykinin (1-100 nM) elicited a transient (5 min) peak of generation of NO that was blocked by the B 2 antagonist HOE 140, whereas B 1 agonist des-Arg 10 -kallidin caused a small linear increase in NO over 20 min. Treatment of HLMVEC with 5 ng/ml interleukin-1β and 200 U/ml interferon-γ for 16 h upregulated B 1 receptors as shown by an approximately fourfold increase in prolonged (>20 min) output of NO in response to des-Arg 10 -kallidin, which was blocked by the B 1 antagonist des-Arg 10 -Leu 9 -kallidin. B 2 receptor agonists bradykinin or kallidin also generated prolonged NO production in treated HLMVEC, which was significantly reduced by either a B 1 antagonist or carboxypeptidase inhibitor, and completely abolished with a combination of B 1 and B 2 receptor antagonists. Furthermore, CPM and CPD activities were increased about twofold in membrane fractions of HLMVEC treated with interleukin-1β and interferon-γ compared with control cells. Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the cell membrane. These data show that cellular Kininase I-type carboxypeptidases can enhance kinin signaling and NO production by converting B 2 agonists to B 1 agonists, especially in inflammatory conditions.
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Kininase ii type enzymes their putative role in muscle energy metabolism
Diabetes, 1996Co-Authors: Tomislav Dragovic, Richard D Minshall, Herbert L Jackman, Lixiu Wang, Ervin G ErdosAbstract:Because of the importance of bradykinin in improving heart function in some conditions or in enhancing glucose uptake by skeletal muscle, we investigated Kininases in these tissues. In P 3 fraction of the heart and skeletal muscles, angiotensin I-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) are the major Kininases, as determined first with specific substrates and second with bradykinin. ACE activity was highest in guinea pig heart (2.7 ± 0.07 μmol·h −1 · mg protein −1 ) but decreased in other species in this order: dog atrium, rat heart, dog ventricle, and human atrium. The specific activity of NEP was lower: 0.45 μmol · h −1 · mg protein −1 in cultured neonatal cardiac myocytes and varying between 0.12 and 0.05 μmol · h −1 · mg protein −1 in human, dog, rat, and guinea pig heart. In the skeletal muscle P 3 , ACE was most active in guinea pig and rat (1.2 and 1.1 μmol · h −1 · mg protein −1 , respectively) but less so in dog (0.09 μmol · h −1 · mg protein −1 ). NEP activity was higher in dog P 3 (0.28 μmol · h −1 · mg protein −1 ) but lower in rat and guinea pig (0.19 and 0.1 μmol · h −1 · mg protein −1 , respectively). Continuous density gradient centrifugation enriched NEP activity in dog and rat (from 0.3 to 1.0 and 0.49 μmol · h −1 · mg protein −1 , respectively). Immunoprecipitation with antiserum to purified NEP proved the specificity of the rat enzyme. Bradykinin (0.1 mmol/1) was inactivated in the presence and absence of inhibitors by rat skeletal muscle NEP, as measured by high-performance liquid chromatography. Here, 36% of the activity was caused by NEP and 19% by ACE. In radioimmunoassay (bradykinin 10 nmol/1), 46 and 55% of Kininase in rat and dog skeletal muscle P 3 , respectively, was due to ACE; 36 and 28%, respectively, was due to NEP. Aside from these enzymes, an aminopeptidase in rat P 3 also inactivates bradykinin. Thus, in conclusion, heart and skeletal muscle membranes contain Kininase II-type enzymes, but their activity depends on the species.
Sakonwun Sangsree - One of the best experts on this subject based on the ideXlab platform.
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Kininase i type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin b1 receptor agonists
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Sakonwun Sangsree, Richard D Minshall, Viktor Brovkovych, Randal A SkidgelAbstract:Kininase I-type carboxypeptidases convert native kinin agonists for B2 receptors into B1 receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carbo...
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Kininase i type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin b1 receptor agonists regulation of cardiovascular signaling by kinins and products of similar converting enzyme systems
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Sakonwun Sangsree, Richard D Minshall, Viktor Brovkovych, Randal A SkidgelAbstract:Kininase I-type carboxypeptidases convert native kinin agonists for B 2 receptors into B 1 receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carboxypeptidase M (CPM) and carboxypeptidase D (CPD) make them ideally situated to regulate kinin activity. Nitric oxide (NO) release from human lung microvascular endothelial cells (HLMVEC) was measured directly in real time with a porphyrinic microsensor. Bradykinin (1-100 nM) elicited a transient (5 min) peak of generation of NO that was blocked by the B 2 antagonist HOE 140, whereas B 1 agonist des-Arg 10 -kallidin caused a small linear increase in NO over 20 min. Treatment of HLMVEC with 5 ng/ml interleukin-1β and 200 U/ml interferon-γ for 16 h upregulated B 1 receptors as shown by an approximately fourfold increase in prolonged (>20 min) output of NO in response to des-Arg 10 -kallidin, which was blocked by the B 1 antagonist des-Arg 10 -Leu 9 -kallidin. B 2 receptor agonists bradykinin or kallidin also generated prolonged NO production in treated HLMVEC, which was significantly reduced by either a B 1 antagonist or carboxypeptidase inhibitor, and completely abolished with a combination of B 1 and B 2 receptor antagonists. Furthermore, CPM and CPD activities were increased about twofold in membrane fractions of HLMVEC treated with interleukin-1β and interferon-γ compared with control cells. Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the cell membrane. These data show that cellular Kininase I-type carboxypeptidases can enhance kinin signaling and NO production by converting B 2 agonists to B 1 agonists, especially in inflammatory conditions.
Michael Bader - One of the best experts on this subject based on the ideXlab platform.
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the role of kinin b1 receptor and the effect of angiotensin i converting enzyme inhibition on acute gout attacks in rodents
Annals of the Rheumatic Diseases, 2016Co-Authors: Cassia Regina Silva, Sara Marchesan Oliveira, Carin Hoffmeister, Vinicius Rafael Funck, Gustavo Petri Guerra, Gabriela Trevisan, Raquel Tonello, Mateus Rossato, Joao Bosco Pesquero, Michael BaderAbstract:Objective Verify the role of the kinin B 1 receptors (B 1 R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents. Methods Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1β levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B 1 R was investigated using pharmacological antagonism or gene deletion. Additionally, B 1 R immunoreactivity in ankle tissue and sensory neurons, Kininase I activity and des-Arg 9 -bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation. Results Kinin B 1 R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B 1 R expression in articular tissues, the content of the B 1 agonist des-Arg 9 -bradykinin and the activity of the B 1 agonist-forming enzyme Kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B 1 R-dependent. Conclusions Kinin B 1 R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B 1 R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.
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Metabolic pathways of Ang peptides.
2014Co-Authors: Robert C. Speth, Eduardo J. Carrera, Catalina Bretón, Andrea Linares, Luz Gonzalez-reiley, Jamala D. Swindle, Kira L. Santos, Ines Schadock, Michael Bader, Vardan T. KaramyanAbstract:Metabolic routes of Ang I and II by neurolysin and other peptidases of the RAS. ACE = angiotensin-converting enzyme, dipeptidyl carboxypeptidase I, Kininase II, EC 3.4.15.1, CD143; ACE-2 = angiotensin-converting enzyme-2, EC 3.4.17.23; APA = aminopeptidase A, glutamyl aminopeptidase, EC 3.4.11.7, CD249; NEP = neprilysin, neutral endopeptidase, EC 3.4.24.11; PRCP = prolyl carboxypeptidase, angiotensinase C, carboxypeptidase P, EC 3.4.16.2; PREP = prolyl endopeptidase, post-prolyl cleaving enzyme, EC 3.4.21.26; TOP = thimet oligopeptidase, EC 3.4.24.15. Adapted from Wright et al. [12].
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kallikrein kinin system in neovascularization
Arteriosclerosis Thrombosis and Vascular Biology, 2009Co-Authors: Michael BaderAbstract:The formation of new blood vessels is viewed completely differently by cardiologists than by oncologists and ophthalmologists. Whereas the former try to stimulate this process, the latter put all efforts into blocking it. In any case, factors involved in neovascularization are of highest therapeutic relevance. The article by Stone et al in this issue of ATVB 1 corroborates that the kallikrein–kinin system (KKS) is one very important but yet underestimated player in this process. This peptide hormone system acts via kinins which are generated from precursors, called kininogens, by enzymes called kallikreins, two of which exist, plasma (PK) and tissue kallikrein (TK). The most important kinin is the nonapeptide bradykinin, which activates the G protein–coupled receptor B2. When Kininase I (carboxypeptidase M or N) truncates the peptide by 1 amino acid at the C terminus, the resulting des-Arg9bradykinin binds the B1 receptor. Interestingly, this receptor is 1 of the rare G protein–coupled receptors, which is inducible by inflammatory mediators, in contrast to the B2 receptor, which is constitutively expressed in multiple cell types.2 Kininase II degrades kinins further to inactive fragments and is identical to angiotensin-converting enzyme (ACE). Consequently ACE inhibitors, one of the most popular classes of cardiovascular drugs, not only inhibit angiotensin generation but also stabilize kinins with important consequences in particular in their effects on vessel formation. See accompanying article on page 657 The first evidence for a role of the KKS in neovascularization was published already more than 15 years ago. Hu and Fan3 showed that bradykinin increases angiogenesis in a sponge implantation model through the B1 receptor. This explained earlier puzzling findings showing that angiotensin II as well as ACE inhibitors increase vessel density in …
