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Biomedical subjects

F Marceau

Publications and source records attributed to F Marceau.

At least 37 records · Page 2Linked to original sources
PubMed1998

Kinin receptors.

Rapid developments are expected in the molecular pharmacology of both B1, and B2 types of kinin receptors, since the underlying genetic structures are now known and widely studied. The consequences of kinin receptor duality and physiopathological regulation have not yet been fully appreciated. Medicinal chemistry is also an active front of research in kinin pharmacology, as more effective drugs targeted at kinin receptors are regularly reported. Various complementary molecular approaches (the receptor binding, cloning, immunoreacting, mutagenesis, inactivation, the study of regulation, allelic polymorphisms, and so forth) are expanding our knowledge of the role of kinins in allergy, inflammation, and singularly, renal medicine.

Amino Acid Sequence↗
PubMed1998

Altered frequency of a promoter polymorphic allele of the kinin B1 receptor gene in inflammatory bowel disease.

BACKGROUND & AIMS: Evidence of kinin-mediated inflammation in the gastrointestinal tract is accumulating. The genes and some polymorphic sites have been characterized for both kinin B1 and B2 receptors. These candidate genes were studied for their possible association with inflammatory bowel disease (IBD). METHODS: In a retrospective study, the prevalence of allele pairs for four polymorphic sites of the two kinin receptor genes was determined in 53 patients with IBD and in 110 healthy volunteers similar in age, body weight, and gender proportions, using polymerase chain reaction and other techniques. RESULTS: Only the B1 receptor promoter polymorphism (G-699-->C) exhibited a significantly different allele frequency between the two groups (prevalence of the C allele of 5.7% in patients with IBD compared with 33.6% in controls; P = 0.0002) or between the controls and either etiologic subgroup (ulcerative colitis and Crohn's disease). Allelic polymorphisms affecting exon 3 of the B1 receptor gene (A1098-->G) or exon 2 (C181-->T) or 1 (a 9-base pair deletion) of the B2 receptor gene were found to be neutral. CONCLUSIONS: The gene corresponding to the B1 receptor for kinins may be a nonetiologic marker of symptomatic IBD, as suggested by the altered prevalence of a polymorphism presumably affecting its regulation.

Adult↗
PubMed1998

Down-regulation of interleukin-1beta production and PGE2 accumulation by an indomethacin-phenylalanine derivative in human monocytes.

This study was initiated to investigate the mechanism of action of a new indomethacin derivative, indomethacin-phenylalanine (indo-Phe) in human monocytes. We determined the effect of indo-Phe on the induction by LPS of prostaglandin-E2 (PGE2) and interleukin-1beta (IL-1beta) production in human monocytes. Indomethacin and indo-Phe inhibited the PGE2 synthesis in treated and untreated IL-1beta or LPS-treated monocytes. Furthermore, in IL-1beta and LPS-treated monocytes, prostaglandin G/H synthase-1 (PGHS-1) protein expression was down-regulated with indomethacin or its indo-Phe analog whereas the level of the inducible protein (PGHS-2) was up-regulated. We analyzed the effect of indomethacin and indo-Phe on the expression of IL-1beta protein in LPS-treated monocytes and found that indo-Phe blocked the LPS-induction of IL-1beta synthesis while indomethacin did not. These differential effects of indomethacin and indo-Phe suggest that two independent ways are involved in the stimulation of monocytes by LPS: the PGHS-2 protein induction and the IL-1beta secretion.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Characterization of two polymorphic sites in the human kinin B1 receptor gene: altered frequency of an allele in patients with a history of end-stage renal failure.

On the basis of the genomic structure of the human B1 receptor (B1R) for kinins, the presence of possible allelic polymorphisms of this gene was investigated using restriction fragment-length polymorphism and single-strand conformation polymorphism. The frequencies of the found alleles were determined in healthy volunteers and in patients with a history of end-stage renal failure, because there is evidence for a nephroprotective action of the kallikrein-kinin system. An A1098-->G polymorphism has been identified in exon 3 in a minority of volunteer blood donors, and is located 35 nucleotides downstream from the stop codon and 14 nucleotides upstream from the polyadenylation signal. The frequency of the G allele is 4.4% in the control sample and not significantly altered in patients with a history of end-stage renal failure. A second and more frequent polymorphism (18.1% of the alleles in the control group, prevalence of 33.3%) consists of a single base substitution (G-699-->C) in the putative promoter region. This polymorphism is significantly less frequent in the population of renal failure patients (prevalence of 20.6%) and determines an increased activity of the promoter function in constructions involving a reporter gene. The altered prevalence of this allele was also found in some etiologic subgroups of uremic patients. This study confirms the mapping of the B1R gene to 14q32. Other investigators have mapped the bradykinin B2 receptor (B2R) gene to a close site on human chromosome 14. A previously described B2R polymorphism (exon 2, C181-->T) had an allele frequency of 9.7% in the control sample and appears to be clinically neutral. The polymorphism of the B1R promoter may be a marker of prognostic significance for the preservation of renal function in diseased individuals.

Adult↗
PubMed1997

Human kallikrein hK2 has low kininogenase activity while prostate-specific antigen (hK3) has none.

In the present paper, we determined the kinin-releasing activity of human prostatic kallikrein hK2 and compared it to one of the kallikreins hK1 and prostate specific antigen (hK3). Kinin-like substances active on the rabbit jugular vein were progressively produced when nanomolar concentrations of hK2 were incubated with heated plasma. However in these experiments, hK1 appeared much more potent than hK2 while hK3 was totally inactive. When hK2 was incubated with purified high molecular weight kininogen, several peptides were generated as shown by the analysis on C18 reverse-phase HPLC. Kinin activity was localized exclusively in a small peak having an elution time identical to that of bradykinin while the only important peak obtained with hK1 corresponded to Lys-bradykinin. Finally, the rate of kinin production of hK2 was found to be more than a thousandfold lower than that of hK1. These experiments show that kallikreins hK2 has only a low kininogenase activity. However, it is not excluded that some of the peptides produced by hK2 action could have other types of biological activity.

Animals↗
PubMed1997

Mechanisms of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells.

Antimalarials are beneficial therapeutic agents in systemic lupus and rheumatoid arthritis. These autoimmune diseases have abnormally low apoptosis of inflammatory cells. Both disorders have an abnormal angiogenesis. In the present report, antimalarials were demonstrated to selectively increase apoptosis of HUVECs in vitro. A 24-h exposure to 50 or 150 microM of the drugs was associated with a significant loss of substrate-adherent cells. Chloroquine exhibited an inhibitory effect on HUVEC proliferation over 7 days. Programmed cell death in HUVECs rendered nonadherent by chloroquine was confirmed by the induction of DNA fragmentation in floating cells. Northern blot analysis revealed a rapidly increased expression of the bcl-x(s) gene without any change in the expression of the bcl-2 gene, indicating that HUVECs under chloroquine were undergoing apoptosis. The onset of the apoptotic cascade in HUVECs appeared shortly after the addition of chloroquine. The effect of chloroquine on apoptosis was distinct from acute cell lysis and was restricted to HUVECs. Antimalarials also induced IL-1alpha production. In parallel, chloroquine alone did not increase the expression of IL-6. Anti-IL-1alpha Ab or IL-1Ra only marginally reversed chloroquine-induced depression of proliferation for the low drug concentration, but not the massive cell death effect at and above 50 microM. Taken together, these data may indicate that antimalarials repress angiogenesis. The autocrine mechanism involving IL-1alpha accounts only for a minor fraction of the full antiendothelial effect of chloroquine, which is mainly dependent on apoptosis.

Antimalarials↗
PubMed1997

Oxidative stress-induced actin reorganization mediated by the p38 mitogen-activated protein kinase/heat shock protein 27 pathway in vascular endothelial cells.

Vascular endothelial cells are constantly in contact with oxyradicals and must be especially well equipped to resist their toxic effects and generate appropriate physiological responses. Despite the importance of oxyradicals in the physiopathology of the vascular endothelium, the mechanisms regulating the oxidative response of endothelial cells are poorly understood. In the present study, we observed that H2O2 in concentrations that induced severe fragmentation of F-actin in fibroblasts rather induced a reorganization of F-actin in primary cultures of human umbilical vein endothelial cells (HUVECs) that was characterized by the accumulation of stress fibers, the recruitment of vinculin to focal adhesions, and the loss of membrane ruffles, H2O2 also induced in these cells a strong (10- to 14-fold) activation of the p38 mitogen-activated protein (MAP) kinase, which resulted in activation of MAP kinase-activated protein kinase-2/3 and phosphorylation of the F-actin polymerization modulator, heat shock protein 27 (HSP27). The MAP kinases extracellular-regulated kinase, and c-Jun N-terminal kinase/stress-activated protein kinase were only slightly increased by these treatments. Inhibiting p38 activity with the highly specific inhibitor SB203580 blocked the H2O2-induced endothelial microfilament responses. Moreover, fibroblasts acquired an endothelium-like SB203580-sensitive actin response when HSP27 concentration was increased by gene transfection to the same high level as found in HUVECs. The results indicate that activation of p38 MAP kinase in cells such as endothelial cells, which naturally express high level of HSP27, plays a central role in modulating microfilament responses to oxidative stress. Consequently, the p38 MAP kinase pathway may participate in the several oxyradical-activated functions of the endothelium that are associated with reorganization of microfilament network.

Actins↗
PubMed1997

Cardiovascular effects of Sar-[D-Phe8]des-Arg9-bradykinin, a metabolically protected agonist of B1 receptor for kinins, in the anesthetized rabbit pretreated with a sublethal dose of bacterial lipopolysaccharide.

We investigated the mechanism of the hypotensive effect of Sar-[D-Phe8]des-Arg9-bradykinin (BK) in lipopolysaccharide-treated anesthetized rabbits. The study involved pharmacokinetic and hemodynamic measurements and tests of antagonism with various drugs. The rate of elimination of Sar-[D-Phe8]des-Arg9-BK from the rabbit plasma was slower than that of Lys-BK, a naturally occurring B1 agonist. The amplitude of the hypotensive effect of Sar-[D-Phe8]des-Arg9-BK was not affected by pretreatment with indomethacin, diclofenac, dazmegrel, NG-nitro-L-arginine, glibenclamide, MK-886, BN-50739, atropine or propranolol, but its duration was shortened by indomethacin and diclofenac. Sar-[D-Phe8]des-Arg9-BK-induced hypotension was associated with decreases of total peripheral resistance, cardiac output, carotid, mesenteric and femoral blood flow, transient reductions followed by secondary increases of vascular resistance in the carotid and femoral beds, reductions of central venous pressure, but no change of hematocrit. Animal pretreatment with diclofenac or hexamethonium abolished the secondary increases of carotid bed vascular resistance caused by the B1 agonist. These and other results suggest that peripheral vasodilation leading to a decrease of total peripheral resistance and a decrease of cardiac output may both contribute consecutively to the hypotensive effect of Sar-[D-Phe8]des-Arg9-BK in this animal model. Inappropriate compensatory responses to arterial hypotension, prostaglandin release, and slow rate of elimination of Sar-[D-Phe8]des-Arg9-BK from the rabbit plasma, may all be at the basis of the prolonged duration of the hypotension caused by the B1 agonist.

Anesthesia↗
PubMed1997

Is there a role for bradykinin in the therapeutic and side effects of angiotensin-converting enzyme inhibitors?

OBJECTIVE: To review critically the persistent suggestion that at least a part of the beneficial and side effects of angiotensin I converting enzyme inhibitors (ACEIs) is derived from the potentiation of endogenous bradykinin (BK). DATA SOURCES: Selected clinical studies of the pharmacology and analytical biochemistry of the kallikrein-kinin system, current literature on novel drugs binding to receptors for BK and angiotensin II, and a few animal studies when clinical data were not available. DATA EXTRACTION: Current concepts of the kallikrein-kinin system and related analytical/pharmacological tools are briefly reviewed and applied to the analysis of the role of endogenous kinins in the therapeutic and side effects of ACEIs. DATA SYNTHESIS: The development of effective BK antagonists is recent and provides novel opportunities to assess the role of BK in physiology and pathology. The role of BK as an inflammatory mediator is relatively well understood, and current drug development programs for kinin receptor agonists and antagonists are focused on the inflammatory pharmacological profile of kinins. The kallikrein-kinin system may not be active to a significant degree in normal individuals, but rather recruited during tissue injury or by specific physiological conditions (such as high sodium intake). The role of BK in some inflammatory/anaphylactoid side effects of ACEIs is not firmly established, but possible. The role of BK in the therapeutic effects of ACEIs depends on the model in animal studies and is likely to be modest in essential hypertension. CONCLUSION: Several methodological problems have delayed the progress of clinical research of the kallikrein-kinin system. While ACEIs clearly potentiate the tissue effects of exogenous BK, the role of endogenous BK in the normal and pathological circulation is still uncertain.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

The kinin B1 receptor: an inducible G protein coupled receptor.

The B1 receptor, selectively stimulated by des-Arg9 fragments of native kinins, has a place in the vast family of G protein coupled receptors. We discuss a series of six criteria useful for comparing the B1 receptor with the more prominent and studied bradykinin B2 receptor. The B1 receptor has attracted interest because it is rapidly upregulated in biological systems following some types of tissue injury, notably the injection of bacterial materials to rabbits, rats, or pigs. A fast and specific genetic program recruits the expression of what we know now to be a G protein coupled receptor in smooth muscle cells, endothelial cells, fibroblasts, and a few other cell types. The cytokine network has been linked to B1 receptor expression in functional experiments, and this may be related to the recent finding of potential cytokine response elements in the proposed gene promoter of the human B1 receptor gene. The experimental approach of B1 receptor mRNA transcriptional regulation, protein synthesis, and maturation is illustrated, based on the biochemical (Northern blot) and functional analysis of isolated organs from rabbits injected with bacterial lipopolysaccharide or incubated in vitro with or without interleukin-1.

Animals↗
PubMed1996

Evidence for vascular tone regulation by resident or infiltrating leukocytes.

The normal vascular wall contains resident leukocytes, notably tissue macrophages (histiocytes) and mast cells, that confer a rapid, eicosanoid-dependent vasoconstrictor response to agonists typical of leukocytes, such as the complement-derived anaphylatoxin C5a or the formylated peptide f-Met-Leu-Phe (isolated organ methodology). The eicosanoid-dependent vasomotor response is even more intense in pathologies that involve leukocyte infiltration of the blood vessel wall, such as atherosclerosis and serum sickness in the rabbit. The leukocyte compartment of the blood vessel is the likely source of vasoactive mediators (eicosanoids, radicals, cytokines) of physiopathological importance, with possible application in cardiac ischemia, lupus nephritis, vasculitides, and graft rejection. This line of investigation may be compared to the discovery and characterization of endothelium-dependent vasomotor responses. However, the problem is experimentally more demanding: histological correlations, experiments based on leukocyte depletion, reconstitution, and enrichment are useful approaches to document this form of circulatory control.

Animals↗
PubMed1996

Structure and genomic organization of the human B1 receptor gene for kinins (BDKRB1).

Two subtypes of mammalian bradykinin receptors, B1 and B2 (BDKRB1 and BDKRB2), have been defined based on their pharmacological properties. The B1 type kinin receptors have weak affinity for intact BK or Lys-BK but strong affinity for kinin metabolites without the C-terminal arginine (e.g., des-Arg9-BK and Lys-des-Arg9-BK, also called des-Arg10-kallidin), which are generated by kininase I. The B1 receptor expression is up-regulated following tissue injury and inflammation (hyperemia, exudation, hyperalgesia, etc.). In the present study, we have cloned and sequenced the gene encoding human B1 receptor from a human genomic library. The human B1 receptor gene contains three exons separated by two introns. The first and the second exon are noncoding, while the coding region and the 3'-flanking region are located entirely on the third exon. The exon-intron arrangement of the human B1 receptor gene shows significant similarity with the genes encoding the B2 receptor subtype in human, mouse, and rat. Sequence analysis of the 5'-flanking region revealed the presence of a consensus TATA box and of numerous candidate transcription factor binding sequences. Primer extension experiments have shown the existence of multiple transcription initiation sites situated downstream and upstream from the consensus TATA box. Genomic Southern blot analysis indicated that the human B1 receptor is encoded by a single-copy gene.

Animals↗
PubMed1996

Pathologic leukocyte infiltration of the rabbit aorta confers a vasomotor effect to chemotactic peptides through cyclooxygenase-derived metabolites.

We determined the effect of chemotactic peptides FMLP and C5a, postulated to be relatively selective activators of phagocytes, on the thoracic aorta of rabbits subjected to experimental pathologies that allowed infiltration by leukocytes, i.e., dietary atherosclerosis and serum sickness. Aortic ring tissues isolated from hypercholesterolemic rabbits, precontracted or not by phenylephrine, exhibited a rapid and relatively sustained (10 to 20 min) contractile response when challenged by FMLP (10 nM and above); precontracted tissues also responded to C5a (2.5 nM and above). Aortic rings from rabbits with serum sickness (13 days post-BSA injection) exhibited brief contractions that were often followed by a relaxation in phenylephrine-precontracted tissues. In both models, tissues from normal weight-matched animals were not consistently responsive to these peptides. The cyclooxygenase inhibitor indomethacin extensively reduced the contractile effect of either peptide on precontracted aortic rings in both models. Chemotactic peptide-induced increased prostanoid secretion was evident only in the fluid bathing atherosclerotic aortic rings. Morphologic correlations included the demonstration of cells positive for the RAM-11 macrophage marker and the C5a receptors in tissues from rabbits with hypercholesterolemia (numerous clusters of cells) or serum sickness (modest infiltration). Control aortic rings responded to FMLP by a significant contraction if cultured for 2 h in the presence of resident peritoneal cells (84% macrophages), but not in the presence of a high density of PBL (less than 0.5% monocytes). Infiltrating or adherent macrophages in the blood vessel wall confer to some phagocyte activating peptides the role of eicosanoid-dependent vasoconstrictor agents.

Animals↗
PubMed1996

Mechanism of the contractile effect of diaspirin-cross-linked hemoglobin in rat isolated aorta strip denuded of endothelium as revealed using an oil-immersion procedure.

Diaspirin-cross-linked hemoglobin (DCLHb) is a chemically modified hemoglobin (Hb) (i.e., alpha-subunits are cross-linked by a covalent bond) currently being tested as a potential oxygen-carrying blood substitute. It was examined for possible vasoactive properties, using the rat isolated aorta strip denuded of endothelium. In this experimental model, DCLHb (1.6-155 microM) was found to be inactive as a vasoconstrictor when added to the Krebs medium but to elicit contractile responses once the Krebs medium containing DCLHb was replaced by mineral oil, a procedure that favors the sequestration of a fixed amount of DCLHb within a substantially reduced volume of extracellular fluid. The contractile activity of DCLHb in our experimental model (i.e., prior exposure of tissues to drugs in the Krebs medium followed by replacement of the Krebs medium by mineral oil) was mimicked by methemoglobin and metmyoglobin, but not by cytochrome c, albumin, hemin, hematin, Fe2+, and a variety of hemorphins. It was abolished by indomethacin, SQ-29548 (prostaglandin H2-thromboxane A2 receptor antagonist), thiourea, or N-2-mercaptopropionylglycine (MCPG), reduced partially by verapamil, but not affected by dazmegrel, MK-886 (leukotriene biosynthesis inhibitor), dimethylsulfoxide, vitamin C or E, deferoxamine, NG-nitro-L-arginine, naloxone, and a variety of other drug receptor antagonists (e.g., prazosin) and protease inhibitors (e.g., pepstatin). Rat aorta strips denuded of endothelium exhibited contractile responses to arachidonic acid added in the Krebs medium (i.e., with no mineral oil added afterwards). Such contractile activity was reduced by SQ-29548, thiourea, or MCPG. Addition of U-46619 (prostaglandin H2-thromboxane A2 mimetic) to the Krebs medium also elicited contractile responses in rat aorta strips denuded of endothelium. Such contractile activity was reduced by SQ-29548, thiourea, or verapamil but not by MCPG. Within the limitations of our experimental approach, these results suggest that (1) the contractile activity of DCLHb in rat aorta strips denuded of endothelium following replacement of the Krebs medium by mineral oil involves the participation of a secondary mediator, which could be a vasoconstrictor metabolite of arachidonic acid; (2) the participation of reactive oxygen species, potential degradation products of DCLHb (e.g., heme, Fe2+, hemorphins), or other mediators in the contractile activity of DCLHb is unlikely; and (3) Ca2+ entry into target cells might be involved in the process by which DCLHb elicits its contractile activity in our experimental model.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Quantification of des-Arg9-bradykinin using a chemiluminescence enzyme immunoassay: application to its kinetic profile during plasma activation.

There is a renewed interest in the kininase I pathway of kinin metabolism, because des-Arg9-bradykinin (des-Arg9-BK) and des-Arg10-Lys-BK are selective and potent agonists of the B1 receptors, that are apparently upregulated by tissue injury. We have developed a polyclonal rabbit antiserum against des-Arg10-Lys-BK. In a radioimmunoassay for des-Arg10-Lys-BK, this antiserum exhibited high specificity. Notably, native kinins with the C-terminal Arg residue, bradykinin (BK) and Lys-BK, did not cross-react to a significant extent, whereas des-Arg9-BK and digoxigenin (DIG)-des-Arg9-BK exhibited a complete cross-reactivity. The antibodies were used to set up a sensitive chemiluminescence enzyme immunoassay (CLEIA) using the DIG-anti-DIG system as intermediate for the revelation of the immune complexes. The detection limit and the half-maximal saturation concentration for des-Arg9-BK were 27 and 1530 fmol/ml respectively. This assay, as well as another for BK quantification, have been applied in vitro to rabbit plasma activated by kaolin. The conversion of BK into des-Arg9-BK was generally efficient, and the persistence and concentration of both peptides were increased in the presence of enalaprilat an inhibitor of the angiotensin converting enzyme (ACEI). Rabbits treated with bacterial lipopolysaccharide exhibited an increase of plasma immunoreactive des-Arg9-BK that was potentiated in animals also treated with ACEI. This CLEIA for des-Arg9-BK is a new analytical tool applicable to analyze of the kininase I metabolites of kinins in vitro and in vivo. Measurements of des-Arg9-BK may be useful indicators of the kallikrein-kinin system activation.

Amino Acid Sequence↗
PubMed1995

Development of a binding assay for the B1 receptors for kinins.

A novel binding assay to kinin B1 receptors was developed, based on the design of a high-affinity agonist ligand, [125I]Tyr-Gly-Lys-Aca-Lys-des-Arg9-BK. Binding to rabbit aortic smooth muscle cells is highly temperature-dependent (optimal at 37 degrees C); apparent binding equilibrium is reached within 30 min, and competition by kinin analogs reveals the expected correlation with the B1 receptor pharmacology. The dissociation constant (Kd) of the labeled ligand is approx. 0.2 nM and this value does not change significantly as a function of cytokine pretreatment. However, the receptor abundance (Bmax) is significantly increased (1.5-fold) by pretreating the cells with interleukin-1 (IL-1), while oncostatin M (OSM) produces a marginal increase of the Bmax. This assay may be useful in documenting the regulation of B1 receptors in pathology.

Amino Acid Sequence↗
PubMed1995

Kinin B1 receptors: a review.

The kinin B1 receptor has been initially defined as the one mediating the contractile effect of bradykinin (BK)-related peptides in the isolated rabbit aorta. The B1 receptor is selectively sensitive to kinin metabolites without the C-terminal arginine residue, e.g. des-Arg9-BK and Lys-des-Arg9-BK; it is apparently rapidly up-regulated in immunopathology under the influence of cytokines and is further regulated by growth factors. Progress in the understanding of this pharmacologic entity is reviewed, including the development of B1 receptor agonists and antagonists, binding assays, physiopathological applications and the recent cloning and sequencing of the receptor cDNA.

Amino Acid Sequence↗