npc-17731 and icatibant

npc-17731 has been researched along with icatibant* in 10 studies

Other Studies

10 other study(ies) available for npc-17731 and icatibant

ArticleYear
Antagonist-induced intracellular sequestration of rabbit bradykinin B(2) receptor.
    Hypertension (Dallas, Tex. : 1979), 2000, Volume: 35, Issue:6

    In a contractility assay based on the rabbit jugular vein, the structurally related drugs NPC 17731 or icatibant (1 to 3 nmol/L) were insurmountable antagonists of bradykinin (BK) B(2) receptors (B(2)Rs). After ample washing (3 hours), the antagonism exerted by these peptides was not reversible. By contrast, the antagonist LF 16. 0687 (30 to 100 nmol/L) was competitive and reversible. A rabbit B(2)R-green fluorescent protein (B(2)R-GFP) conjugate was expressed in mammalian cells. In COS-1 cells, it exhibited an affinity for [3H]BK (K(D)=1.61 nmol/L) similar to that of the wild-type rabbit B(2)R. The stably expressed construction in HEK-293 cells was functionally active (phospholipase A(2) assay), and the antagonists mentioned above retained their respective surmountable or insurmountable behavior. Competition of [(3)H]BK binding to B(2)R-GFP by the antagonists or BK was largely reversible after a 3-hour washout period at 0 degrees C; at 37 degrees C, icatibant or NPC 17731 effects were not reversible. B(2)R-GFP was visualized in the plasma membranes of HEK-293 cells and rapidly internalized in response to BK. NPC 17731 or icatibant slowly translocated B(2)R-GFP into cells over 24 hours, whereas LF 16.0687 had no effect on the subcellular distribution of B(2)R-GFP. Cell extract immunoblotting with anti-GFP antibodies revealed a 101- to 105-kDa protein that was not significantly degraded on 24 hours of cell treatment with any of the ligands but was translocated in part to the 15 000-g pellet of the extract on treatment with BK or the noncompetitive antagonists. NPC 17731 and icatibant are noncompetitive, nonequilibrium antagonists that promote the cellular sequestration of rabbit B(2)R expressed in an heterologous system.

    Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Cell Line; COS Cells; Green Fluorescent Proteins; Humans; In Vitro Techniques; Indicators and Reagents; Intracellular Membranes; Jugular Veins; Luminescent Proteins; Oligopeptides; Rabbits; Receptor, Bradykinin B2; Receptors, Bradykinin; Recombinant Fusion Proteins; Vasoconstriction

2000
Spontaneous human B2 bradykinin receptor activity determines the action of partial agonists as agonists or inverse agonists. Effect of basal desensitization.
    The Journal of biological chemistry, 1999, Oct-15, Volume: 274, Issue:42

    In this report, we show that desensitization regulates ligand-independent, spontaneous activity of the human B2 bradykinin (BK) receptor, and the level of spontaneous receptor activity determines the action of the BK antagonists and partial receptor agonists NPC17731 and HOE140 as agonists or inverse agonists. Spontaneous receptor activity was monitored by measuring basal cellular phosphoinositide (PI) hydrolysis as a function of the density of the receptor in transiently transfected HEK293 cells. Minimal spontaneous activity of the wild-type B2 receptor was detected in these cells. Mutating a cluster of serines and threonines within the fourth intracellular domain of the receptor, which is critical for agonist-promoted desensitization, significantly increased the spontaneous receptor activity. BK, the natural B2 receptor ligand and, consequently, a full agonist, stimulated PI hydrolysis at high and low levels of spontaneous receptor activity. On the other hand, the partial agonists NPC17731 and HOE140 were stimulatory, or agonists, at the lower level of receptor activity but inhibitory, or inverse agonists, at the higher level of activity. These results show that receptors are desensitized in response to their spontaneous activity. Furthermore, these results, which refute traditional theories, show that the capacity of a drug to modulate a receptor response is not intrinsic to the drug but is also dependent on the cellular environment in which the drug acts.

    Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Cell Line; Humans; Mutagenesis; Oligopeptides; Receptor, Bradykinin B2; Receptors, Bradykinin

1999
Bradykinin BK2 receptors contribute to reflex cardiovascular responses during brief abdominal ischemia.
    The American journal of physiology, 1998, Volume: 274, Issue:1

    Ischemically sensitive visceral sympathetic nerve fibers, which are thought to represent the afferent limb of a strong cardiovascular pressor reflex, can be stimulated by exogenously applied bradykinin (BK). During ischemia, BK also is known to be produced locally and to serve as an endogenous stimulus for activation of ischemically sensitive nerve endings. It is unclear, however, whether ischemically induced BK production is sufficient to elicit a reflex cardiovascular response. Accordingly, femoral arterial and venous catheters were positioned in anesthetized cats, and the superior mesenteric and celiac arteries were isolated for placement of snare occluders. After dual occlusion of these arteries (20 min), one of two chemically dissimilar specific kinin B2 (BK2) receptor antagonists, HOE-140 (30-40 micrograms/kg iv, n = 8) or NPC-17731 (30-40 micrograms/kg iv, n = 11), was administered and dual occlusion was repeated. The reflex rise of mean arterial blood pressure (BP) of 16 +/- 3.7% was significantly (P < 0.05) reduced by HOE-140 to 8.4 +/- 2.0%. NPC-17731 similarly attenuated the reflex BP increment from 13 +/- 1.2 to 6.2 +/- 1.6% (P < 0.05). In a separate set of control animals the first and second periods of ischemia induced reflex BP increments that did not differ significantly (16 +/- 2.7 and 16 +/- 5.7%, respectively). Qualitatively similar decrements of the BP response were produced by the BK2 receptor antagonists in two additional groups in which blood flow to the superior mesenteric and celiac arteries was diverted to a venous reservoir to eliminate the initial transient (mechanically induced) rise in BP associated with artery ligation that is known not to be associated with the reflex response. These results indicate that the stimulation of BK2 receptors on visceral afferent nerves by BK is responsible, at least in part, for the reflex cardiovascular response during visceral ischemia.

    Topics: Abdomen; Animals; Baroreflex; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cats; Celiac Artery; Female; Ganglia, Sympathetic; Ischemia; Male; Mesenteric Arteries; Oligopeptides; Receptors, Bradykinin

1998
Effect of WIN 64338, a B2 bradykinin receptor antagonist on guinea-pig tracheal smooth muscle cells in culture.
    Fundamental & clinical pharmacology, 1998, Volume: 12, Issue:2

    This study investigated the effect of the non-peptidic B2 bradykinin (BK) receptor antagonist WIN 64338 on BK binding and BK-induced inositol phosphate formation on guinea-pig tracheal smooth muscle cells in culture. The presence of specific and saturable binding sites for BK was demonstrated using [3H]BK. Scatchard analysis indicates a single population of binding sites for [3H]BK with a maximal density (Bmax) of 245.4 +/- 71 fmol/mg of protein and an equilibrium dissociation constant (Kd) of 87.7 +/- 0.12 pM. The order of potency of] B2 BK receptor ligands was Hoe 140 = NPC 17731 > BK > WIN 64338 > D- Arg0[Hyp3, D-Phe7]-BK > > des-Arg9-BK, while B1 BK receptor antagonist, des-Arg9-[Leu8]-BK, was without effect on [3H]BK binding. These results demonstrate the presence of B2 Bk receptors on cultured tracheal smooth muscle cells. The cells were stimulated by BK, and inositol phosphate formation was determined by anion exchange chromatography. The stimulating effect of BK on inositol phosphate formation was concentration dependent (1 nM to 10 microM). The B1 BK agonist des-Arg9-BK did not induce inositol phosphate formation. The order of potency of B2 antagonists to inhibit BK-induced inositol phosphate formation was Hoe 140 = NPC 17731 > WIN 64338 > D-Arg0[Hyp3, D-Phe7]-BK. This study demonstrates that WIN 64338 is able to displace [3H]BK binding and to inhibit B2-BK-induced inositol phosphate formation on cultured guinea-pig tracheal smooth muscle cells.

    Topics: Adrenergic beta-Antagonists; Analgesics; Animals; Binding, Competitive; Bradykinin; Bradykinin Receptor Antagonists; Cells, Cultured; Fluorescent Antibody Technique; Guinea Pigs; Inositol Phosphates; Male; Muscle, Smooth; Naphthalenes; Oligopeptides; Organophosphorus Compounds; Receptor, Bradykinin B2; Receptors, Bradykinin; Trachea

1998
Characterization of des-Arg9-bradykinin-induced contraction in guinea-pig gallbladder in vitro.
    European journal of pharmacology, 1997, Jul-16, Volume: 331, Issue:1

    We have reported that bradykinin induces graded contraction in guinea-pig gallbladder in vitro through activation of bradykinin B2 receptors and prostanoid release, while des-Arg9-bradykinin, a selective bradykinin B1 receptor agonist, causes only a weak contraction, suggesting the presence of badykinin B1 receptors in this tissue. In the present study, we attempted to characterise the receptor subtype and the possible mechanism by which des-Arg9-bradykinin induces contraction in this preparation. Contractions induced by des-Arg9-bradykinin in guinea-pig gallbladder (1 pM to 1 microM) increased significantly as a function of time elapsed after setting up of the preparation, reaching the maximum after 6 h of equilibration (EC50 16.4 pM and Emax 0.6 +/- 0.08 g). Des-Arg9-bradykinin-induced contraction in guinea-pig gallbladder was totally prevented by cycloheximide (70 microM, an inhibitor of protein synthesis), indomethacin (3 microM), ibuprofen (30 microM), phenidone (30 microM) or Ca2+-free medium plus EGTA, and was partially antagonised by MK 571 ((3-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3-oxo-propyl) thio) methyl) propanoic acid, 0.1 microM) or by nicardipine (1 microM), but was not affected by dazoxiben (30 microM), staurosporine (100 nM) or L 655,240 (240 (3-[1-(4-clorobenzil)-5-fluoro-3-metilhyindol-2il] 2,2-dimetilpropanoic acid, 1 microM). Unexpectedly, des-Arg9-bradykinin-induced contraction was unaffected by the selective bradykinin B1 receptor antagonists, des-Arg9-[Leu8]-bradykinin and des-Arg9-NPC 17761 (des-Arg0-D-Arg [Hip3, D-HipE (transtiofenil)7, Oic8]-des-Arg9-bradykinin). However, the selective bradykinin B2 receptor antagonists, HOE 140 (D-Arg0-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) and NPC 17731 (D-Arg0 [Hyp3, DHypE (transpropyl)7, Oic8]-bradykinin), completely blocked des-Arg9-bradykinin-mediated contraction. Pre-treatment of the animals with Escherichia coli endotoxin (lipopolysaccharide, 30 microg/animal, i.v., 24 h) did not significantly change the response to des-Arg9-bradykinin induction. It is concluded that des-Arg9-bradykinin-induced contractions in guinea-pig gallbladder are mediated primarily by the release of proinflammatory eicosanoid(s) derived from the cyclo-oxygenase pathway. These effects are unrelated to thromboxane A2 and do not seem to be coupled to activation of a protein kinase C-dependent mechanism. Response to des-Arg9-bradykinin increases as a function of the equilibration period of

    Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Calcium; Dose-Response Relationship, Drug; Gallbladder; Guinea Pigs; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Oligopeptides; Prostaglandins; Protein Kinase C; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin

1997
Pro-inflammatory effects induced by bradykinin in a murine model of pleurisy.
    European journal of pharmacology, 1997, Jul-16, Volume: 331, Issue:1

    Bradykinin caused a dose-related increase in cell influx 4 h after its administration into the mouse pleural cavity (ED50 = 3.2 nmol/cav., 95% confidence limits = 0.6-15.5). Cell influx peaked at 4 h and remained elevated for up to 72 h, whereas exudation was detected between 2 and 6 h after bradykinin administration. Both HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7, Oic8]bradykinin) and NPC 17731 (D-Arg0-[Hyp3 D-HypE(transpropyl7)Oic8]bradykinin) inhibited bradykinin-induced cell influx (ID50 0.028 (0.05-0.16) and 0.4 (0.3-0.7) pmol/cav., respectively). Des-Arg9-[Leu8]bradykinin (0.1 and 3.0 nmol/cav., 30 min before) did not inhibit the effects of bradykinin. Pre-treatment of animals with either indomethacin, terfenadine, dexamethasone, N(omega)-nitro-L-arginine benzyl ester, cromolyn, theophylline, salbutamol, FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]N-met hyl-N-phenyl-methyl-3-(2-naphthyl)-L-alaninamide) or SR 142801 ((N)-(1-[3-[1-benzoyl-3-(3,4-dichloro-phenyl)-piperidin-3-yl]pr opy l]-4-phenyl-piperidin-4-yl)-N-methyl-acetamide) significantly inhibited cell migration (P < 0.01). These results indicate that bradykinin had a significant pro-inflammatory effect on the pleural cavity of the mice. This effect seems to be primarily mediated via activation bradykinin B2 receptors which trigger the release of other mediators.

    Topics: Animals; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Cell Movement; Dipeptides; Dose-Response Relationship, Drug; Female; Indoles; Inflammation; Leukocyte Count; Male; Mice; Neutrophils; Oligopeptides; Piperidines; Pleura; Pleurisy; Receptor, Bradykinin B2; Time Factors

1997
Endogenous BK stimulates ischemically sensitive abdominal visceral C fiber afferents through kinin B2 receptors.
    The American journal of physiology, 1994, Volume: 267, Issue:6 Pt 2

    Abdominal ischemia and reperfusion reflexly activate the cardiovascular system. In the present study, we evaluated the role of endogenously produced bradykinin (BK) in the stimulation of ischemically sensitive visceral afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of abdominal ischemia. Abdominal ischemia increased the portal venous plasma BK level from 49 +/- 10 to 188 +/- 66 pg/ml (P < 0.05). Injection of BK (1 microgram/kg ia) into the descending aorta significantly increased impulse activity (0.88 +/- 0.16 impulses/s) of 10 C fibers, whereas a kinin B1-receptor agonist, des-Arg9-BK (1 microgram/kg), did not alter the discharge rate. Inhibition of kininase II activity with captopril (4 mg/kg i.v.) potentiated impulse activity of 14 ischemically sensitive C fibers (0.44 +/- 0.09 vs. precaptopril, 0.33 +/- 0.08 impulses/s; P < 0.05). In addition, a kinin B2-receptor antagonist (NPC-17731; 40 micrograms/kg i.v.) attenuated activity of afferents during ischemia (0.39 +/- 0.08 vs. pre-NPC-17731, 0.72 +/- 0.13 impulses/s; P < 0.05) and eliminated the response of 10 C fibers to BK. Another kinin B2-receptor antagonist, Hoe-140 (30 micrograms/kg iv), had similar inhibitory effects on six other ischemically sensitive C fibers. In 15 separate cats treated with aspirin (50 mg/kg i.v.), Hoe-140 (30 micrograms/kg i.v.) attenuated impulse activity of only 3 of 16 ischemically sensitive C fibers. These data suggest that BK produced during abdominal ischemia contributes to the stimulation of ischemically sensitive visceral C fiber afferents through kinin B2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Afferent Pathways; Animals; Aspirin; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Cats; Ischemia; Nerve Fibers; Oligopeptides; Portal Vein; Receptors, Bradykinin; Viscera

1994
Antagonists of bradykinin that stabilize a G-protein-uncoupled state of the B2 receptor act as inverse agonists in rat myometrial cells.
    The Journal of biological chemistry, 1994, Oct-21, Volume: 269, Issue:42

    Several B2 bradykinin (BK) receptor-specific antagonists including HOE140, NPC17731, and NPC567 exhibited negative intrinsic activity, which was observed as a decrease in basal phosphoinositide hydrolysis in primary cultures of rat myometrial cells, and this response was opposite to that elicited by the agonist BK. The order of potency of the antagonists in attenuating basal activity was essentially the same as that in competing both [3H]BK and [3H]NPC17731 for binding to B2 receptors on both intact rat myometrial cells and bovine myometrial membranes. We previously proposed a three-state model for the binding of agonists to G-protein-coupled B2 receptors in bovine myometrial membranes (Leeb-Lundberg, L. M. F. and Mathis, S. A. (1990) J. Biol. Chem. 265, 9621-9627). This model was based on the ability of BK to promote the sequential formation of three receptor binding states where formation of the third, equilibrium state was blocked by Gpp(NH)p (guanyl-5'-yl imidodiphosphate) identifying it as the G-protein-coupled state of the receptor. Here, we show that, in contrast to BK, these antagonists bound preferentially to a G-protein-uncoupled state of the receptor. These results indicate that B2 receptor antagonists that stabilize a G-protein-uncoupled state of the receptor act as inverse agonists. Furthermore, these results provide strong evidence that endogenous G-protein-coupled receptors exhibit spontaneous activity in their natural environment in the absence of agonist occupancy.

    Topics: Amino Acid Sequence; Animals; Bradykinin; Cells, Cultured; Female; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Molecular Sequence Data; Myometrium; Oligopeptides; Rats; Receptors, Bradykinin

1994
Bradykinin contributes to the exercise pressor reflex: mechanism of action.
    Journal of applied physiology (Bethesda, Md. : 1985), 1993, Volume: 75, Issue:5

    This study determined the receptors responsible for mediating bradykinin's effect on skeletal muscle afferents that cause the pressor reflex in anesthetized cats. In eight cats, 1 microgram of bradykinin was injected intra-arterially into the gracilis muscle before and after intravenous injection of a kinin B2-receptor antagonist (NPC 17731, 20 micrograms/kg). Initial injection of bradykinin reflexly increased mean arterial pressure by 23 +/- 7 mmHg, maximal change in pressure over time by 439 +/- 272 mmHg/s, and heart rate by 11 +/- 4 beats/min. The hemodynamic response to bradykinin was abolished by kinin B2-receptor blockade. Similar injection of the kinin B1-receptor agonist des-Arg9-bradykinin caused no cardiovascular responses (n = 6). In eight different animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses to 30 s of electrically stimulated hindlimb contraction were attenuated by 50 +/- 6, 55 +/- 7, and 41 +/- 8%, respectively, after kinin B2-receptor blockade. In eight other animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses were reduced by 58 +/- 8, 66 +/- 6, and 40 +/- 12%, respectively, after inhibition of prostaglandin synthesis with indomethacin (2.5-3 mg/kg iv) and were then abolished by subsequent B2-receptor blockade. These data suggest that bradykinin contributes to the exercise pressor reflex through its action on kinin B2 receptors located on the nerve endings of the muscle afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Gas Analysis; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cats; Female; Hindlimb; Indomethacin; Male; Muscle Contraction; Muscles; Neurons, Afferent; Oligopeptides; Physical Exertion; Prostaglandin Antagonists; Receptors, Bradykinin; Reflex

1993
Kinin antagonists.
    Lancet (London, England), 1991, Oct-19, Volume: 338, Issue:8773

    Topics: Amino Acid Sequence; Animals; Bradykinin; Humans; Kinins; Molecular Sequence Data; Oligopeptides; Peptides; Shock, Septic

1991