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1.
Respir Res ; 22(1): 281, 2021 Oct 30.
Article in English | MEDLINE | ID: mdl-34717626

ABSTRACT

BACKGROUND: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. METHODS: Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. RESULTS: Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1ß, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, ßMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. CONCLUSIONS: We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins.


Subject(s)
Kinins/antagonists & inhibitors , Neointima/pathology , Pulmonary Arterial Hypertension/pathology , Pulmonary Artery/pathology , Tunica Intima/pathology , Vascular Remodeling/drug effects , Animals , Disease Models, Animal , Humans , Male , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/metabolism , Pulmonary Artery/drug effects , Rats , Rats, Wistar , Tunica Intima/drug effects
2.
Clin Rev Allergy Immunol ; 51(2): 183-92, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27207174

ABSTRACT

Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare but medically significant disease that can be associated with considerable morbidity and mortality. Research into the pathogenesis of HAE-C1-INH has expanded greatly in the last six decades and has led to new clinical trials with novel therapeutic agents and treatment strategies. Mechanisms of pharmacotherapy include (a) supplementing C1-INH, the missing serine-protease inhibitor in HAE; (b) inhibiting the activation of the contact system and the uncontrolled release of proteases in the kallikrein-kinin system, by blocking the production/function of its components; (c) inhibiting the fibrinolytic system by blocking the production/function of its components; and (d) inhibiting the function of bradykinin at the endothelial level. Strategies for managing HAE-C1-INH are aimed at treating acute attacks, or preventing attacks, through the use of prophylactic treatment. Available agents for treating acute attacks include plasma-derived C1-INH concentrates, a recombinant C1-INH, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor. Long-term prophylactic treatments include attenuated androgens, plasma-derived C1-INH concentrates, and anti-fibrinolytics. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are already approved for self-administration at home. The number of management options for HAE-C1-INH has increased considerably within the past decade, thus helping to alleviate the burden of this rare disease.


Subject(s)
Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/etiology , Angioedemas, Hereditary/metabolism , Angioedemas, Hereditary/prevention & control , Antifibrinolytic Agents/therapeutic use , Bradykinin Receptor Antagonists/therapeutic use , Complement C1 Inhibitor Protein/therapeutic use , Disease Progression , Humans , Kallikreins/antagonists & inhibitors , Kinins/antagonists & inhibitors , Premedication
3.
Biochem Pharmacol ; 88(1): 12-22, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24384116

ABSTRACT

Ischemia/reperfusion injury (IRI) may occur from ischemia due to thrombotic occlusion, trauma or surgical interventions, including transplantation, with subsequent reestablishment of circulation. Time-dependent molecular and structural changes result from the deprivation of blood and oxygen in the affected tissue during ischemia. Upon restoration of blood flow a multifaceted network of plasma cascades is activated, including the complement-, coagulation-, kinin-, and fibrinolytic system, which plays a major role in the reperfusion-triggered inflammatory process. The plasma cascade systems are therefore promising therapeutic targets for attenuation of IRI. Earlier studies showed beneficial effects through inhibition of the complement system using specific complement inhibitors. However, pivotal roles in IRI are also attributed to other cascades. This raises the question, whether drugs, such as C1 esterase inhibitor, which regulate more than one cascade at a time, have a higher therapeutic potential. The present review discusses different therapeutic approaches ranging from specific complement inhibition to simultaneous inhibition of plasma cascade systems for reduction of IRI, gives an overview of the plasma cascade systems in IRI as well as highlights recent findings in this field.


Subject(s)
Blood Coagulation , Complement Inactivator Proteins/therapeutic use , Complement System Proteins/metabolism , Reperfusion Injury/blood , Animals , Antibodies, Monoclonal/therapeutic use , Blood Coagulation/drug effects , Blood Coagulation/physiology , Clinical Trials as Topic , Complement Inactivator Proteins/pharmacology , Complement System Proteins/immunology , Endothelium, Vascular/drug effects , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Humans , Kinins/antagonists & inhibitors , Kinins/immunology , Reperfusion Injury/drug therapy , Reperfusion Injury/immunology , Reperfusion Injury/pathology , Thromboplastin/antagonists & inhibitors , Thromboplastin/immunology , Treatment Outcome
4.
Rev Alerg Mex ; 56(2): 48-55, 2009.
Article in Spanish | MEDLINE | ID: mdl-19526954

ABSTRACT

BACKGROUND: Hereditary angioedema is an autosomal dominant inherited condition that is characterized by the local development of edema of the skin, subcutaneous tissue, and the walls of almost any organ, including the gastrointestinal and upper respiratory tracts. OBJECTIVE: To describe the clinical characteristics, diagnosis and treatment of six controlled patients with hereditary angioedema. PATIENTS AND METHODS: This paper presents clinical characteristics of six patients, four of them members of the same family, and two, isolated, non-family related cases. This contribution is a review of the latest literature related to diagnosis and treatment of hereditary angioedema. RESULTS: Hereditary angioedema is a rare clinical entity that has a complicated manifestation profile that requires to discard a wide series of differential diagnosis. Deeper knowledge of its genetics and physiopathology will allow us to explore new treatment alternatives in addition to those already available. CONCLUSIONS: By diffusion of isolated cases or familial cases series, as presented in this paper, the disease recognition and timely treatment will be reached.


Subject(s)
Angioedemas, Hereditary , Adolescent , Algorithms , Angioedemas, Hereditary/diagnosis , Angioedemas, Hereditary/genetics , Angioedemas, Hereditary/pathology , Angioedemas, Hereditary/therapy , Bradykinin/analogs & derivatives , Bradykinin/therapeutic use , Complement C1 Inhibitor Protein/therapeutic use , Danazol/therapeutic use , Disease Progression , Female , Humans , Kinins/antagonists & inhibitors , Male , Pedigree , Peptides/therapeutic use , Young Adult
5.
Neurotherapeutics ; 6(1): 28-42, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19110197

ABSTRACT

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.


Subject(s)
Brain Injuries/drug therapy , Animals , Brain Edema/drug therapy , Brain Edema/physiopathology , Brain Injuries/physiopathology , Cyclosporine/therapeutic use , Dronabinol/analogs & derivatives , Dronabinol/therapeutic use , Erythropoietin/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Kinins/antagonists & inhibitors , Magnesium/therapeutic use , Minocycline/therapeutic use , Mitochondria/drug effects , Mitochondria/physiology , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Oxidative Stress/physiology , Progesterone/therapeutic use , Psychotropic Drugs/therapeutic use , Thyrotropin-Releasing Hormone/therapeutic use , Toll-Like Receptors/agonists
6.
Indian J Exp Biol ; 45(11): 949-53, 2007 Nov.
Article in English | MEDLINE | ID: mdl-18072538

ABSTRACT

The kinins are implicated in the pathogenesis of scorpion envenomation. Therefore, this study was carried out to examine the involvement of kinins for the ECG abnormalities induced by M. tamulus concanesis, (BT) venom in anaesthetized rats. ECG was recorded using needle electrodes with limb lead II configuration. The PR interval, QRS wave pattern, QRS duration, ST segment and heart rate were examined in saline only, venom alone, and venom after aprotinin groups. BT venom (5 mg/kg) produced heart block of varying degree and ischemia-like changes in ECG wave pattern and the animals died within 30 min after exposure to venom. In aprotinin pretreated animals, the initial ECG changes produced by venom persisted, but after 15 min the ECG pattern improved and the animals survived for the entire period of observation (120 min). The results indicate that aprotinin protected the rats against the cardiotoxicity induced by BT venom.


Subject(s)
Aprotinin/therapeutic use , Heart Block/prevention & control , Myocardial Ischemia/prevention & control , Scorpion Venoms/toxicity , Animals , Aprotinin/administration & dosage , Electrocardiography , Heart Block/chemically induced , Heart Block/metabolism , Heart Block/physiopathology , Heart Rate/drug effects , Kinins/antagonists & inhibitors , Male , Myocardial Ischemia/chemically induced , Myocardial Ischemia/metabolism , Myocardial Ischemia/physiopathology , Rats , Scorpions
7.
FEBS J ; 274(16): 4271-86, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17645545

ABSTRACT

Two plasma kallikrein-kinin system inhibitors in the salivary glands of the kissing bug Triatoma infestans, designated triafestin-1 and triafestin-2, have been identified and characterized. Reconstitution experiments showed that triafestin-1 and triafestin-2 inhibit the activation of the kallikrein-kinin system by inhibiting the reciprocal activation of factor XII and prekallikrein, and subsequent release of bradykinin. Binding analyses showed that triafestin-1 and triafestin-2 specifically interact with factor XII and high molecular weight kininogen in a Zn2+-dependent manner, suggesting that they specifically recognize Zn2+-induced conformational changes in factor XII and high molecular weight kininogen. Triafestin-1 and triafestin-2 also inhibit factor XII and high molecular weight kininogen binding to negatively charged surfaces. Furthermore, they interact with both the N-terminus of factor XII and domain D5 of high molecular weight kininogen, which are the binding domains for biological activating surfaces. These results suggest that triafestin-1 and triafestin-2 inhibit activation of the kallikrein-kinin system by interfering with the association of factor XII and high molecular weight kininogen with biological activating surfaces, resulting in the inhibition of bradykinin release in an animal host during insect blood-feeding.


Subject(s)
Insect Proteins/genetics , Kallikrein-Kinin System/drug effects , Salivary Glands/metabolism , Salivary Proteins and Peptides/genetics , Triatoma/genetics , Amino Acid Sequence , Animals , Blood Coagulation/drug effects , Cloning, Molecular , DNA, Complementary/chemistry , DNA, Complementary/genetics , Dose-Response Relationship, Drug , Electrophoresis, Polyacrylamide Gel , Factor XII/antagonists & inhibitors , Factor XII/chemistry , Factor XII/metabolism , Insect Proteins/metabolism , Insect Proteins/pharmacology , Kinetics , Kinins/antagonists & inhibitors , Kinins/blood , Molecular Sequence Data , Molecular Weight , Phylogeny , Plasma Kallikrein/antagonists & inhibitors , Prekallikrein/antagonists & inhibitors , Prekallikrein/chemistry , Prekallikrein/metabolism , Protein Binding/drug effects , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacology , Salivary Proteins and Peptides/metabolism , Salivary Proteins and Peptides/pharmacology , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Triatoma/metabolism , Whole Blood Coagulation Time , Zinc/pharmacology
8.
Handb Exp Pharmacol ; (177): 181-216, 2007.
Article in English | MEDLINE | ID: mdl-17087124

ABSTRACT

Neuropeptides and kinins are important messengers in the nervous system and--on the basis of their anatomical localisation and the effects produced when the substances themselves are administered, to animals or to human subjects-a significant number of them have been suggested to have a role in pain and inflammation. Experiments in gene deletion (knock-out or null mutant) mice and parallel experiments with pharmacological receptor antagonists in a variety of species have strengthened the evidence that a number of peptides, notably substance P and calcitonin gene-related peptide (CGRP), and the kinins have a pathophysiological role in nociception. Clinical studies with non-peptide pharmacological antagonists are now in progress to determine if blocking the action of these peptides might have utility in the treatment of pain.


Subject(s)
Analgesics, Non-Narcotic/pharmacology , Kinins/antagonists & inhibitors , Neuropeptides/antagonists & inhibitors , Analgesics, Non-Narcotic/therapeutic use , Animals , Animals, Genetically Modified/physiology , Calcitonin Gene-Related Peptide Receptor Antagonists , Humans , Kinins/physiology , Neurokinin-1 Receptor Antagonists , Neuropeptides/physiology , Pain/drug therapy , Receptors, Neurokinin-1/genetics , Substance P/antagonists & inhibitors
9.
Article in Spanish | CUMED | ID: cum-38648

ABSTRACT

Muy a pesar de la existencia de variados grupos de fármacos m antimaláricos, en muchas partes del mundo continúan siendo fármacos de primera línea para le tratamiento de la malaria o paludismo la quinina y sus congéneres. Dado que esa patología es capaz de afectar al se humano expuesto en cualquier etapa de la vida , la posibilidad de interacción de los fármacos antimaláricos conjuntamente con cualquier otro tipo de medicación, ya por la presencia en en el paciente afecto de la malaria, de alguna otra patología, sea esta de caracter agudo o crónico , nos motivaron a la ejecución de la presente revisión , sumándole a ellos además variadas reacciones adversas de importancia clínica. En lo que respecta al embarazo y lactancia podemos considerar que, en general , la mayoría de estos antimaláricos son seguros eficaces durante el embarazo, no constituyendo este estado fisiológico una contraindicación absoluta para su empleo, sin embargo, debe valorarse en cada caso la reacción riesgo/ beneficio(AU)


Despite the existence of variet groups of antimalarial drugs Quinine and its structural similarities keep on being first line druds in the treatment of malaria in most part of the world. Because yhis disease can affect human beings at any time in life and there is also a real possibility of antimalarial drug interaction, adding up clinically important varied adverse drud reactions. These issues led the authors into the current bibliographic investigation. regarding pregnancy and breast feeding it is considered that most of antimalarial druds are safe with lesss potential harm during this physiological state. Pregnancy is not an absolute contraindication in using such drugs. Howerver in each patient the relationship risk/benefit should be assessed(AU)


Subject(s)
Humans , Female , Pregnancy , Quinine/adverse effects , Quinine/pharmacology , Kinins/antagonists & inhibitors
10.
Georgian Med News ; (140): 54-62, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17179590

ABSTRACT

The aim is to show the effectiveness of inhibitors of the kallikrein-kinin system (KKS) to avoid early microcirculation impairment and low reperfusion damages in the ischemic area during systemic thrombolysis (T) in order to achieve optimal results of thrombolytic therapy (TLT) in patients with acute myocardium infarction. Patients (n=104) with acute myocardium infarction were divided into 4 groups: treatment with early TLT infusing Contrycal (Aprotinin) and Heparin (CH) during the first 2 hrs from the onset of disease (Gr. 1); treatment for isolated T at an early stage (Gr. 2); TLT with late T (in 3-6 hrs) (Gr. 3); and conventional therapy (Gr. 4). The dynamics of clinical and ECG data were evaluated for each of the groups. Before the clinical study was fully evaluated, an experimental-morphological, controlled study was carried out on dogs. These results showed improved retrograde blood flow of the acute ischemized myocardium and decrease in ischemia level, together with reduction of frequency and area of reperfused intramiocardial haemorrhages (RPIMH) in infarction areas under the TLT and CH infusion. When CH was infused a significant advantage was revealed in early T that showed high antianginal and antiarrhythmic effect, while no Q wave was observed or it was deepened non-significantly. More clinical dynamic problems with extrasystols and significant deepening of Q wave were seen in the earlier isolated T (Gr. 2) that were worse than those seen in Gr. 1 conditions, but the problems were more negative in the patients from Gr. 3 and 4. CH optimizes the situation causing suppression of the pathological activation of KKS, decreasing vessel permeability, and reducing reperfusion damage. The latest thrombolytic drugs ensure faster thromb lysing but do not prevent the reperfusion damage, as higher fibrinolytic activity at the moment of T causes enhanced activation of KKS and RPIMH development and prevents peroxide oxidation of the lipids but this may result in higher affectivity of antioxidant use. Earlier administration of KKS inhibitors optimizes the affectivity of TLT and widens the indication to the systemic and intracoronary T, minimizes complications, and may cause higher affectivity of coronary angioplasty (CAP) and aorta-coronary shunting in patients with acute myocardium infarction.


Subject(s)
Aprotinin/therapeutic use , Fibrinolytic Agents/adverse effects , Kinins/antagonists & inhibitors , Myocardial Infarction/drug therapy , Myocardial Reperfusion Injury/chemically induced , Myocardial Reperfusion Injury/prevention & control , Thrombolytic Therapy/adverse effects , Adult , Aged , Aprotinin/administration & dosage , Drug Therapy, Combination , Electrocardiography , Fibrinolytic Agents/therapeutic use , Follow-Up Studies , Heparin/adverse effects , Heparin/therapeutic use , Humans , Infusions, Intravenous , Middle Aged , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/physiopathology , Severity of Illness Index , Streptokinase/adverse effects , Streptokinase/therapeutic use , Treatment Outcome , Trypsin Inhibitors
11.
J Periodontal Res ; 41(3): 200-7, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16677289

ABSTRACT

BACKGROUND AND OBJECTIVE: Epidemiological evidence implicates a connection between human periodontitis and systemic diseases. One possible mechanism involves the direct dissemination of periodontopathogens to the target organs through the circulation. The aim of this work was to define the mechanism used by Porphyromonas gingivalis for dissemination from a sequestered infection site. MATERIAL AND METHODS: BALB/c mice were subcutaneously infected with P. gingivalis via use of a mouse chamber model. Tissue fluids from various sites were collected and cultured to determine the presence of P. gingivalis. Evans Blue dye was used to measure the dissemination ability of P. gingivalis. Kinin-associated molecules were introduced into mice, and their effects on bacterial dissemination and mouse pathology were monitored. RESULTS: P. gingivalis strain A7436 caused remote lesions and septicemia with severe cachexia, resulting in animal death. Intrachamber challenge with A7436 resulted in vascular permeability enhancement (VPE), as measured by the systemic infiltration of Evans Blue dye into chamber fluids. VPE was blocked by kininase and kinin receptor antagonist and enhanced by exogenous bradykinin and kininase inhibitor. Live bacteria were recovered from the subcutaneous perichamber and abdominal spaces (spreading), and from the blood (disseminating) of infected mice. Both kininase and kinin receptor antagonist reduced animal mortality as a result of infection with strain A7436 and decreased the number of bacteria recoverable from the blood, but they were not associated with bacterial spreading. CONCLUSIONS: The results suggest that activation of the kinin system is involved in the breach of the vascular barrier that permits dissemination of P. gingivalis.


Subject(s)
Bacteremia/microbiology , Kallikrein-Kinin System/physiology , Porphyromonas gingivalis/physiology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Bacteroidaceae Infections/microbiology , Body Fluids/microbiology , Bradykinin/pharmacology , Cachexia/microbiology , Capillary Permeability/drug effects , Cause of Death , Coloring Agents , Disease Models, Animal , Evans Blue , Female , Focal Infection/microbiology , Kallikreins/pharmacology , Kinins/antagonists & inhibitors , Kinins/pharmacology , Mice , Mice, Inbred BALB C , Peptidyl-Dipeptidase A/pharmacology , Vasodilator Agents/pharmacology
12.
Inflammopharmacology ; 12(5-6): 591-6, 2005.
Article in English | MEDLINE | ID: mdl-16259723

ABSTRACT

Kinin is an important mediator of hyperalgesia, inflammatory conditions and asthma. It causes pain, inflammation, increased vascular permeability and vasodilatation. Several kinin antagonists have been developed with the aim of treating these pathologies. Kinin B2 receptor agonists and kallikrein may have clinical utility in the treatment of hypertension, left ventricular hypertrophy, ischemic heart disease, congestive heart failure and diabetes. However, there is a need to know whether there is a safe therapeutic window between potential cardio-protective and pro-inflammatory effects following administration of kinin B2 receptor agonists.


Subject(s)
Cardiovascular Diseases/physiopathology , Inflammation/physiopathology , Kallikrein-Kinin System/physiology , Animals , Cardiovascular Diseases/prevention & control , Humans , Inflammation/prevention & control , Kallikrein-Kinin System/drug effects , Kinins/antagonists & inhibitors , Kinins/pharmacology , Kinins/therapeutic use , Receptor, Bradykinin B2/agonists , Receptor, Bradykinin B2/physiology
13.
J Pharmacol Sci ; 99(1): 6-38, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16177542

ABSTRACT

The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Kallikrein-Kinin System/drug effects , Kallikrein-Kinin System/physiology , Kallikreins/metabolism , Kinins/metabolism , Angioedema/drug therapy , Angioedema/genetics , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Aprotinin/pharmacology , Aprotinin/therapeutic use , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Bradykinin/therapeutic use , Bradykinin B2 Receptor Antagonists , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/genetics , Complement C1 Inactivator Proteins/deficiency , Complement C1 Inactivator Proteins/genetics , Complement C1 Inhibitor Protein , Humans , Inflammation/drug therapy , Inflammation/genetics , Kallikrein-Kinin System/genetics , Kallikreins/antagonists & inhibitors , Kidney Diseases/drug therapy , Kidney Diseases/genetics , Kinins/agonists , Kinins/antagonists & inhibitors , Neprilysin/antagonists & inhibitors , Neprilysin/metabolism , Peptidyl-Dipeptidase A/metabolism , Polymorphism, Genetic , Pyridines/pharmacology , Pyridines/therapeutic use , Randomized Controlled Trials as Topic , Receptor, Bradykinin B1/genetics , Receptor, Bradykinin B1/metabolism , Receptor, Bradykinin B2/genetics , Receptor, Bradykinin B2/metabolism , Serpins/deficiency , Serpins/genetics , Thiazepines/pharmacology , Thiazepines/therapeutic use
14.
Nihon Rinsho ; 63 Suppl 3: 431-6, 2005 Mar.
Article in Japanese | MEDLINE | ID: mdl-15813106
15.
Regul Pept ; 127(1-3): 207-15, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15680489

ABSTRACT

Bombinakinin M (DLPKINRKGP-bradykinin) is a bradykinin-related peptide purified from skin secretions of the frog Bombina maxima. As previously reported, its biosynthesis is characterized by a tandem repeats with various copy numbers of the peptide and sometimes co-expressed with other structure-function distinguishable peptides. At present study, two novel cDNAs encoding bombinakinin M and its variants were cloned from a cDNA library from the skin of the frog. The encoded two precursor proteins are common in that each contains three repeats of a novel 16-amino acid peptide unit and one copy of kinestatin at their N- and C-terminal parts, respectively. They differ in that the first precursor contains two copies of bombinakinin M and the second one contains one copy of a novel bombinakinin M variant. Bombinakinin M was found to elicit concentration-dependent contractile effects on guinea pig ileum, with an EC50 value of 4 nM that is four times higher than that of bradykinin (1 nM). Interestingly, the synthetic peptide (DYTIRTRLH-amide), as deduced from the 16-amino acid peptide repeats in the newly cloned cDNAs, possessed weak inhibitory activity on the contractile effects of bombinakinin M, but not on that of bradykinin. Furthermore, the newly identified bombinakinin M variant (DLSKMSFLHG-Ile1-bradykinin), did not show contractile activity on guinea pig ileum, but showed potentiation effect on the myotropic activity of bradykinin. In a molar ratio of 1:58, it augmented the activity of bradykinin up to two-fold.


Subject(s)
Anura , Bradykinin/metabolism , Kinins/antagonists & inhibitors , Neuropeptides/antagonists & inhibitors , Peptides/metabolism , Protein Precursors/metabolism , Skin/chemistry , Amino Acid Sequence , Animals , Base Sequence , Bradykinin/genetics , Cloning, Molecular , Gene Library , Humans , Kinins/genetics , Kinins/metabolism , Molecular Sequence Data , Neuropeptides/genetics , Neuropeptides/metabolism , Peptides/genetics , Protein Precursors/genetics , Sequence Alignment
16.
Article in English | MEDLINE | ID: mdl-15638742

ABSTRACT

Bradykinin and Lys-bradykinin are potent peptide mediators implicated in several physiopathological effects in mammals. They act through activation of G-protein-coupled constitutive B(2) or inducible kinin B(1) receptors linked to signaling pathways involving increased intracellular Ca(++) concentrations and/or release of mediators including arachidonic acid metabolites, NO and EDHF. In the cardiovascular system, the kallikrein-kinin system exerts a fine control of vascular smooth muscle tone and arterial blood pressure, and plays a significant cardioprotective effect. This has been lately confirmed in experimental studies employing transgenic mice overexpressing human tissue kallikrein and animals with knockout of kinin B(1) and B(2) receptor gene. Disturbances in this system are associated with arterial hypertension, myocardial ischaemia and other clinical complications. Inhibitors of kininase II (angiotensin-converting enzyme) have been prescribed successfully to patients with cardiovascular diseases, but there is still a great interest in developing drugs or pharmacological strategies that augment the activity of kininogen-kallikrein-kinin system in pathological conditions. Delivery of adenovirus vector containing the human tissue kallikrein gene (gene kallikrein therapy) has emerged as a great potential to satisfy these conditions. This review provides a summary of plasma and tissue kallikrein-kinin system, focusing on the pharmacological properties, kinin receptors and drugs reported to interfere with their actions. The modulatory effects of the kallikrein-kinin system on cardiovascular system, particularly in regulating smooth muscle tone and arterial blood pressure and in preventing myocardium ischaemia have also been explored in the review.


Subject(s)
Bradykinin/physiology , Cardiovascular System/metabolism , Kallikrein-Kinin System/physiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Bradykinin/biosynthesis , Bradykinin/metabolism , Cardiotonic Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Cardiovascular System/drug effects , Genetic Therapy , Humans , Kallidin/biosynthesis , Kallidin/metabolism , Kallikrein-Kinin System/drug effects , Kininogens/metabolism , Kinins/antagonists & inhibitors , Kinins/genetics , Kinins/metabolism , Plasma Kallikrein/antagonists & inhibitors , Plasma Kallikrein/metabolism , Protease Inhibitors/therapeutic use , Tissue Kallikreins/antagonists & inhibitors , Tissue Kallikreins/metabolism
17.
J Clin Pharmacol ; 43(11): 1187-95, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14551172

ABSTRACT

All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction, and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin-converting enzyme inhibitors is primarily mediated via the kinin-releasing pathway, which may cause regression of left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.


Subject(s)
Bradykinin/analogs & derivatives , Cardiovascular Abnormalities/metabolism , Kinins/physiology , Animals , Bradykinin/pharmacology , Bradykinin/therapeutic use , Bradykinin Receptor Antagonists , Cardiovascular Abnormalities/drug therapy , Cardiovascular Abnormalities/physiopathology , Humans , Kinins/antagonists & inhibitors , Receptors, Bradykinin/physiology
18.
Br J Pharmacol ; 139(2): 299-308, 2003 May.
Article in English | MEDLINE | ID: mdl-12770935

ABSTRACT

1 Kinin B(2) receptor antagonists or tissue kallikrein (t-KK) inhibitors prevent oedema formation and associated sequelae in caerulein-induced pancreatitis in the rat. We have now further investigated the mechanism of kinin generation in the pancreas. 2 Kinins were elevated in the pancreatic tissue already before oedema formation became manifest. Peak values (421+/-59 pmol g(-1) dry wt) were reached at 45 min and remained elevated for at least 2 h; a second increase was observed at 24 h. Pretreatment with the B(2) receptor antagonist icatibant abolished kinin formation, while post-treatment was ineffective. 3 Total kininogen levels were very low in the pancreas of controls, but increased 75-fold during acute pancreatitis. This increase was absent in rats that were pretreated with icatibant. 4 During pancreatitis, t-KK-like and plasma kallikrein (p-KK)-like activity in the pancreas, as well as trypsinogen activation peptide (TAP) increased significantly. Icatibant pretreatment further augmented t-KK about 100-fold, while p-KK was significantly attenuated; TAP levels remained unaffected. 5 Endogenous protease inhibitors (alpha(1)-antitrypsin, alpha(2)-macroglobulin) were low in normal tissues, but increased 45- and four-fold, respectively, during pancreatitis. This increase was abolished when oedema formation was prevented by icatibant. 6 In summary, oedema formation is initiated by t-KK; the ensuing plasma protein extravasation supplies further kininogen and active p-KK to the tissue. Concomitantly, endogenous protease inhibitors in the oedema fluid inhibit up to 99% of active t-KK. Our data thus suggest a complex interaction between kinin action and kinin generation involving positive and negative feedback actions of the inflammatory oedema.


Subject(s)
Bradykinin/analogs & derivatives , Edema/physiopathology , Kinins/metabolism , Pancreatitis/physiopathology , Acute Disease , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bradykinin/pharmacology , Ceruletide , Edema/metabolism , Enzyme Activation , Female , Kininogens/metabolism , Kinins/antagonists & inhibitors , Pancreas/metabolism , Pancreatitis/chemically induced , Pancreatitis/metabolism , Plasma Kallikrein/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/antagonists & inhibitors , Serine Proteinase Inhibitors/metabolism , Tissue Kallikreins/metabolism , Trypsinogen/metabolism , alpha 1-Antitrypsin/metabolism , alpha-Macroglobulins/metabolism
19.
Eur J Pharm Biopharm ; 55(2): 147-54, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12637090

ABSTRACT

FK224 is a cyclopeptide drug with a low aqueous solubility. Following oral administration to rats, poor absorption was observed due to proteolysis in the gastrointestinal tract. The objective of this study was to investigate the effect of the pulmonary route on the systemic absorption of FK224 in comparison with other administration routes, and to determine the bioavailability (BA) of FK224 following pulmonary administration in rats using various dosage forms. From absorption studies on the Polyethylene Glycol 400 solution given by various routes (intranasal, subcutaneous, intratracheal and intravenous as reference), it was shown that pulmonary administration was a potentially attractive route for FK224. In the pulmonary absorption studies, after administration of the aqueous suspension, the BA was reduced to 2.7% compared with 16.8% for the solution. However, beta-cyclodextrin (beta-CyD) was found to be an effective additive as far as improving the solubility of FK224 was concerned. The BA of the aqueous suspension containing beta-CyD was increased to 19.2%. Pressurized metered dose inhalers were prepared by formulating beta-CyD with various molar ratios of 1:0, 1:1 and 1:7 (FK224/beta-CyD), and the resulting BAs were 4.3%, 29.0% and 91.2%, respectively. It was observed that both the C(max) and AUC of FK224 were increased as the amount of beta-CyD increased. The plasma profiles showed sustained absorption. In conclusion, we have seen that the lung is a suitable route for absorption of FK224, and beta-CyD is an extremely effective additive as far as improving the pulmonary absorption of FK224 is concerned. beta-CyD or derivatives with various degrees of aqueous solubility are potential drug carriers for controlling pulmonary absorption.


Subject(s)
Cyclodextrins/chemistry , Excipients/chemistry , Lung/metabolism , Peptides, Cyclic/pharmacokinetics , beta-Cyclodextrins , Absorption , Administration, Intranasal , Administration, Oral , Animals , Area Under Curve , Biological Availability , Chemistry, Pharmaceutical , Injections, Subcutaneous , Kinins/antagonists & inhibitors , Male , Particle Size , Peptides, Cyclic/administration & dosage , Peptides, Cyclic/chemistry , Pharmaceutical Solutions , Rats , Rats, Sprague-Dawley , Solubility , Substance P/agonists , Suspensions , Time Factors
20.
Immunopharmacology ; 43(2-3): 219-24, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10596856

ABSTRACT

It was determined earlier that inhibition of the action of endogenous kinins by the bradykinin B2 antagonist, icatibant (Hoe-140; D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), prevents pancreatic oedema formation during caerulein-induced acute pancreatitis, and simultaneously improves the egress of activated pancreatic enzymes from the pancreas. We have now investigated whether inhibition of increases in vascular permeability by another approach, i.e., pretreatment with dexamethasone, would have comparable effects. In addition, preliminary data are presented on the effects of the selective low molecular weight inhibitor of tissue kallikrein, H-(4-Cl)-D-Phe-1Nal-(3-aminopropyl)-guanidine (CH-2856). Icatibant abolished plasma extravasation into the pancreatic tissue and prevented the development of hypovolaemia. Caerulein-induced increases of amylase activity in the pancreas were significantly reduced by icatibant, while amylase activity in blood was augmented. Inhibition of kinin generation by CH-2856 had similar effects, as oedema formation was inhibited and enzyme activities were reduced in the pancreas and augmented in the blood serum. Dexamethasone completely abolished oedema formation, but only partially inhibited the development of hypovolaemia and haemoconcentration. Amylase activities in the pancreas and in blood remained completely unaffected by dexamethasone. The results suggest that retention of activated enzymes in the pancreatic tissue during acute pancreatitis involves a B2 receptor-mediated, but glucocorticoid-insensitive mechanism.


Subject(s)
Capillary Permeability/drug effects , Dexamethasone/pharmacology , Kinins/antagonists & inhibitors , Pancreas/enzymology , Pancreatitis/enzymology , Acute Disease , Amylases/metabolism , Animals , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Edema/prevention & control , Female , Rats , Rats, Sprague-Dawley
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