New synthetic antagonists of bradykinin

Schächter, M; Uchida, Yasuhiro; Longridge, David J; Labedz, Teresa; Whalley, Eric T.; Vavrek, Raymond J.; Stewart, John M.

doi:10.1111/j.1476-5381.1987.tb11390.x

Cited by 74 publications

(35 citation statements)

References 14 publications

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“…Previous studies have indicated that Bk2R mediates bradykinin-induced vascular permeability (24,25). In this report, the C1INH-deficient mice were protected from enhanced vascular permeability by an inhibitor of plasma kallikrein, by a Bk2R antagonist, and by Bk2R-deficiency.…”

Section: Discussionmentioning

confidence: 49%

Increased vascular permeability in C1 inhibitor–deficient mice mediated by the bradykinin type 2 receptor

Han¹,

MacFarlane²,

Mulligan³

et al. 2002

J. Clin. Invest.

176

175

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IntroductionHereditary angioedema (HAE) develops in individuals who are heterozygous for deficiency or dysfunction of C1 inhibitor (C1INH). This disease is characterized by recurrent episodes of angioedema involving the skin or the oropharyngeal, laryngeal, or gastrointestinal mucosa. Prior to the use of attenuated androgens such as danazol and stanazolol as chronic therapy for HAE, as many as one-third of patients died from asphyxiation secondary to laryngeal edema.C1INH belongs to the serpin family of serine protease inhibitors. It is the only inhibitor of C1r and C1s, the classical complement pathway proteases (1). It also regulates kinin generation via inactivation of factors XIIa and plasma kallikrein, and intrinsic coagulation via inactivation of factor XIa (2-6). In HAE, the low levels of active C1INH in plasma lead to unregulated activation of the complement and contact cascades and the development of angioedema with its associated complications. Complement system activation results in decreased levels of C4 and C2, while contact system activation results in cleavage of high molecular weight kininogen.In the past several years a great deal has been learned about the structure, genetics, mechanism of action, and inhibitory spectrum of C1INH. However, the pathophysiology of the increased vascular permeability of HAE has remained controversial for over 30 years. It is believed that angioedema results from uncontrolled activation of either the classical complement pathway with generation of a vasoactive peptide (C2 kinin) released from C2, and/or from contact system activation with release of bradykinin from high-molecular-weight kininogen (7-11). Although the majority of the available data support a role for bradykinin, the critical question is whether bradykinin alone could account for the symptoms of patients with HAE, or other mediators are also involved.To investigate the role of C1INH in vivo, and to determine whether bradykinin is involved in the induction of vascular permeability in edema formation, we obtained mice in which the C1INH gene was targeted for disruption in murine embryonic stem cells using gene trapping (12). Neither homozygous nor heterozygous C1INH-deficient mice had an obvious phenotype. However, when compared with wild-type littermates, these animals clearly had increased vascular permeability that could be reversed by treatment with human C1INH, with an inhibitor of contact system activation (DX88), or with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140). Inhibition of bradykinin inactivation with captopril enhanced vascular permeability in C1INH-deficient mice, but mice doubly deficient in both C1INH and the Bk2R did not demonstrate increased vascular permeability. Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema. Disruption of the C1INH gene by gene trapping enabled the generation of homozygous-and heterozygous-deficient mice. Methods C1INH gene targeting. Mice in which theMating of heterozygous-deficient mice resulted in the expected 1:...

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Section: Discussionmentioning

confidence: 49%

Increased vascular permeability in C1 inhibitor–deficient mice mediated by the bradykinin type 2 receptor

Han¹,

MacFarlane²,

Mulligan³

et al. 2002

J. Clin. Invest.

176

175

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“…2), both B 1 and B 2 receptor signaling may actually enhance angiogenesis. The previous report, which concluded that B 2 receptors were not involved in the enhancement of angiogenesis, was made on the basis of the first-generation B 2 receptor antagonist, a peptide analog of BK, that was not resistant to BKdegrading enzymes, and had a partial agonistic action on B 2 receptors (Hu and Fan, 1993;Schachter et al, 1987). As shown in this experiment, not only the more stable B 2 receptor antagonist, Hoe140, but also the nonpeptide orally active B 2 receptor antagonist, FR173657, significantly reduced angiogenesis (Fig.…”

Section: Angiogenesis and Kininsmentioning

confidence: 99%

Suppressed Angiogenesis in Kininogen-Deficiencies

Hayashi

Aoki

Yoshida

et al. 2002

Laboratory Investigation

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SUMMARY:We investigated whether the kinin-generating system enhanced angiogenesis in chronic and proliferative granuloma and in tumor-surrounding stroma. In rat sponge implants, angiogenesis was gradually developed in normal Brown Norway Kitasato rats (BN-Ki). The development of angiogenesis was significantly suppressed in kininogen-deficient Brown Norway Katholiek rats (BN-Ka). The angiogenesis enhanced by basic fibroblast growth factor was also significantly less marked in BN-Ka than in BN-Ki. Naturally occurring angiogenesis was significantly suppressed by B 1 or B 2 antagonist. mRNA of vascular endothelial growth factor was more highly expressed in the granulation tissues in BN-Ki than in BN-Ka. Daily topical injections of aprotinin, but not of soy bean trypsin inhibitor, suppressed angiogenesis. Daily topical injections of low-molecular weight kininogen enhanced angiogenesis in BN-Ka. Topical injections of serum from BN-Ki, but not from BN-Ka, also facilitated angiogenesis in BN-Ka. FR190997, a nonpeptide mimic of bradykinin, promoted angiogenesis markedly, with concomitant increases in vascular endothelial growth factor mRNA. Angiogenesis in the granulation tissues around the implanted Millipore chambers containing Walker-256 cells was markedly more suppressed in BN-Ka than in BN-Ki. Our results suggest that endogenous kinin generated from the tissue kallikrein-kinin system enhances angiogenesis in chronic and proliferative granuloma and in the stroma surrounding a tumor. Thus, the agents for the kinin-generating system and/or kinin receptor signaling may become useful tools for controlling angiogenesis. (Lab Invest 2002, 82:871-880).

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“…The former preparation has often been used in earlier investigations of this type of drugs (Vavrek & Stewart, 1985;Regoli et al, 1986;Schachter et al, 1987;Steranka et al, 1988), and the latter has been employed because of its high sensitivity to BK. In addition, the rat duodenum was used because it responds to BK with a relaxation by a mechanism which is not yet fully understood, but involves activation of BK receptors (Boschcov et al, 1984;Griesbacher et al, 1989;Pereira & Paiva, 1989;Altinkurt & Oztiirk, 1990).…”

Section: Isolated Smooth Musclesmentioning

confidence: 99%

“…Although the specificity and high potency of these antagonists has been unequivocally established (Regoli et al, 1986;Griesbacher & Lembeck, 1987;Schachter et al, 1987;Steranka et al, 1988;Francel et al, 1989;Griesbacher et al, 1989), their susceptibility to fast enzymatic degradation limited their usefulness (Griesbacher et al, 1989). Now, new analogues of BK have been synthesized in which unusual amino acids have been inserted with the intention of making the antagonists more resistent to enzymatic cleavage.…”

Section: Introductionmentioning

confidence: 99%

New, long‐acting, potent bradykinin antagonists

Lembeck

Griesbacher

Eckhardt

et al. 1991

British J Pharmacology

209

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Hyp3-D-Tic7-Oic8-BK (compound II), and Arg(Tos)'-Hyp3-Thi5-D-Tic7-Oic8-BK (compound III), were tested against the effects of BK in 9 bioassay preparations including visceral smooth muscles, vasoconstriction, plasma protein extravasation, release of prostaglandin E2, bronchoconstriction, and stimulation of afferent C-fibre nociceptors. In some of these tests the effects of the new compounds were compared with those of the antagonist D-Arg0-Hyp2-Thi5'8-D-Phe7-BK (compound IV), described by

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New synthetic antagonists of bradykinin

Cited by 74 publications

References 14 publications

Increased vascular permeability in C1 inhibitor–deficient mice mediated by the bradykinin type 2 receptor

Increased vascular permeability in C1 inhibitor–deficient mice mediated by the bradykinin type 2 receptor

Suppressed Angiogenesis in Kininogen-Deficiencies

New, long‐acting, potent bradykinin antagonists

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