bq-123 and Edema

The aim of this study was to assess whether endothelin-A receptor (ET(A)-R) blocker, BQ123, influences lung edema, lipid peroxidation TBARS), hydrogen peroxide (H(2)O(2)), TNF-α concentration or the glutathione redox system in the lung homogenates obtained from LPS-induced endotoxic shock rats. The study was performed on male Wistar rats (n = 6 per group) divided into groups: (1) saline, (2) LPS (15 mg/kg)-saline, (3) BQ123 (0.5 mg/kg)-LPS, (4) BQ123 (1 mg/kg)-LPS. The ET(A)-R antagonist was injected intravenously 30 min before LPS administration. Five hours after saline or LPS administration, animals were sacrificed and lungs were isolated for indices of lung edema, oxidative stress and TNF-α concentration. Injection of LPS alone resulted in lung edema development and a marked increase in TNF-α (p < 0.02), TBARS (p < 0.02), and H(2)O(2) (p < 0.01) concentrations as well as a depletion of total glutathione (p < 0.01). Administration of BQ123 (1 mg/kg), before LPS challenge, led to a significant reduction in TNF-α and H(2)O(2) concentrations (p < 0.05) and elevation of both total glutathione and the GSH/GSSG ratio (p < 0.05). However, it did not prevent LPS-induced TBARS increase and lung edema formation. Interestingly, a lower dose of BQ123 was much more effective in decreasing H(2)O(2), TBARS, as well as TNF-α levels (p < 0.02, p < 0.05, p < 0.05, respectively). That dose was also effective in prevention of lung edema development (p < 0.01). Taken together, the obtained results indicate that BQ123 is highly effective in decreasing LPS-induced oxidative stress in lungs. Moreover, the dose of 0.5 mg/kg of the antagonist showed to be more effective in decreasing free radical generation and lung edema in endotoxemic rats.

Topics: Animals; Dose-Response Relationship, Drug; Edema; Endothelin A Receptor Antagonists; Free Radicals; Glutathione; Hydrogen Peroxide; Lipid Peroxidation; Lipopolysaccharides; Lung; Male; Oxidative Stress; Peptides, Cyclic; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Endothelin-1 causes ET(A) receptor-mediated enhancement of capsaicin-induced nociception in mice. We have assessed if this hyperalgesic effect of endothelin-1 is also accompanied by other pro-inflammatory effects, namely nociception and oedema, and characterized the endothelin ET receptors involved. Intraplantar (i. pl.) hind-paw injection of endothelin-1 (0.3 - 30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20. 5+/-3.3 s; endothelin-1 at 30 pmol, 78.1+/-9.8 s), largely confined to the first 15 min. Endothelin-1 (1 - 10 pmol) potentiated ipsilateral capsaicin-induced (0.1 microgram, i.pl.; at 30 min) nociception (vehicle, 40.2+/-2.6 s; endothelin-1 at 10 pmol, 98.4+/-5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3+/-2.3 mg; endothelin-1 at 30 pmol, 100.3+/-6.1 mg). Selective ET(B) receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin-3 (up to 30 pmol) induced only modest oedema. ET(A) receptor antagonists BQ-123 (1 nmol, i.pl. ) or A-127722-5 (6 micromol kg(-1), i.v.) prevented all effects of endothelin-1 (10 pmol), but the ET(B) receptor antagonist BQ-788 (1 or 10 nmol, i.pl.) was ineffective. BQ-788 (10 nmol, i.pl.) unveiled hyperalgesic effects of 30 pmol endothelin-1 and endothelin-3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin-1-induced (10 pmol) nociception or oedema, but abolished hyperalgesia. Thus, endothelin-1 triggers ET(A) receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw. Simultaneous activation of ET(B) receptors by endothelin-1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, effects of the peptide.

Topics: Animals; Atrasentan; Capsaicin; Edema; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hyperalgesia; Male; Mice; Nociceptors; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Viper Venoms

1. The relative contribution of ETA and ETB receptors in the response of rat skin to endothelins was investigated by use of the selective ETB agonist IRL-1620 and the selective ETA antagonist BQ-123. 2. Binding data suggest the presence of ETA and ETB receptors as preincubation with [Ala3,11,18Nle7]-endothelin-1 reduced ET-1 binding by approximately 40%. 3. Intradermal injection of endothelin-1 (ET-1, 1-10 pmol/site) and ET-3 (3-100 pmol/site) induced a dose-dependent decrease in local blood flow assessed by 133Xe clearance at test sites in rat skin. 4. The endothelin analogue [Ala3,11,18Nle7]-ET-1 (30-1000 pmol/site) induced significant vasoconstriction (P < 0.05) at the highest doses used and the selective ETB receptor agonist, IRL-1620 [Suc[Glu9,Ala11,15] endothelin (8-21)], (0.01-100 pmol/site) acted in a potent manner to induce a significant (P < 0.01) dose-dependent decrease in 133Xe clearance. 5. Co-injection with the selective ETA receptor antagonist, BQ-123 (1 nmol/site), completely abolished the vasoconstriction to ET-1 and partially to ET-3, but had no effect on IRL-1620-induced vasoconstriction. In addition, IRL-1620 responses were not altered at sites treated with submaximal doses of a nitric oxide synthase inhibitor or a prostaglandin synthase inhibitor. 6. ET-1 and IRL-1620 (100 fmol-1 pmol/site) did not induce oedema formation as measured by [125I]-albumin accumulation in the presence or absence of the vasodilator, calcitonin gene-related peptide (CGRP). ET-1 (1-3 pmol/site) inhibited substance P-induced oedema formation and this effect,suggested to be secondary to a vasoconstrictor effect, was significantly reversed by BQ-123 (1 nmol/site).7. The findings in this study indicate that there are ETA and ETB receptors in rat skin and agents which activate either receptor act to mediate a decrease in cutaneous blood flow, but have no effect on increased microvascular permeability.

Topics: Animals; Arginine; Capillary Permeability; Edema; Endothelins; In Vitro Techniques; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Peptides, Cyclic; Rats; Receptors, Endothelin; Regional Blood Flow; Skin; Vasoconstriction

This study investigated the influence of the selective endothelin (ET) ETA receptor antagonists BQ-123 and FR 139317 on paw edema induced by ovalbumin (OVA) injection (3 micrograms/paw) to OVA-sensitized mice [50 micrograms in 5 mg of Al(OH)3, s.c., 14 days earlier]. Injections of BQ-123 (1.5, 15, and 150 pmol/paw, 15 min earlier) reduced OVA-induced edema from 59.6 +/- 4.0 to 48.3 +/- 5.4, 44.6 +/- 3.8, and 34 +/- 2.0 microliters, respectively (p < 0.05; n = 6). Like BQ-123, FR 139317 (7.5, 75, and 750 pmol/paw) also inhibited OVA-induced edema in a graded fashion but was less potent. In contrast, BQ-123 (150 pmol/paw) failed to affect paw edema induced in nonsensitized mice by histamine (100 micrograms/paw), serotonin (100 micrograms/paw), or zymosan (500 micrograms/paw), but significantly reduced edema induced by carrageenan (300 micrograms/paw) by 30% (p < 0.05). These results strongly suggest that endogenous ETs, acting through ETA receptors, play an important proinflammatory role in the allergic reaction to OVA.

Topics: Animals; Azepines; Edema; Endothelin Receptor Antagonists; Endothelins; Indoles; Male; Mice; Ovalbumin; Peptides, Cyclic; Receptor, Endothelin A