tcv-309 and icatibant

The injection of lipopolysaccharide (LPS) from E. Coli into the dorsal skin of rats caused a dose-dependent increase in vascular permeability as measured by the extravasation over a 40-min period of intravenously injected dye. This increase caused by LPS was attenuated by pretreatment with the bradykinin (BK) receptor antagonist HOE140, the selective platelet-activating factor (PAF) antagonist TCV309, and by combined treatment with mepyramine and methysergide. Combined treatment with HOE140 and TCV309 resulted in further suppression than that achieved with a single treatment alone. By the simultaneous pretreatment with all antagonists, the response was almost totally abolished. On the other hand, indomethacin also inhibited the response induced by LPS, but not those induced by BK and PAF itself. A small dose of BK or histamine synergistically potentiated the effect of PAF when simultaneously injected. These results suggest that BK, PAF, histamine/serotonin and prostaglandins are involved in the LPS-induced increase in vascular permeability, where PAF, in addition to its direct action, potentiates the response to BK and histamine, and prostaglandins potentiate the actions of other mediators without its direct action.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Dose-Response Relationship, Drug; Drug Synergism; Escherichia coli; Extravasation of Diagnostic and Therapeutic Materials; Histamine; Histamine H1 Antagonists; Indomethacin; Isoquinolines; Lipopolysaccharides; Male; Methysergide; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pyridinium Compounds; Pyrilamine; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Skin; Specific Pathogen-Free Organisms; Tetrahydroisoquinolines

1. The aim of this study was to clarify the role of endogenous bradykinin (BK) in the hypotensive response induced by lipopolysaccharide (LPS) by comparing the degree of hypotension caused by LPS in a strain of specific pathogen-free (SPF) Brown Norway (B/N), kininogen-deficient mutant Katholiek rats with that of B/N normal Kitasato rats. 2. The dose-dependent hypotensive responses caused by intravenous injection of BK (1-100 nmol kg-1) or platelet-activating factor (PAF, 0.003-1 microgram kg-1), were not different in the two strains of rats used. However, there was a strong difference in the hypotensive response induced by LPS in kininogen-deficient and normal rats; in normal rats the hypotensive response was composed of two phases (15 min and 70-80 min after LPS injection), but in kininogen-deficient rats LPS caused a delayed (second phase), but not an acute (first phase) hypotension. 3. We demonstrate that Hoe 140 (1 mg kg-1, i.v.) is a potent, selective, and long-lasting antagonist of the hypotensive effects of BK. Hoe 140 diminished the hypotension caused by LPS in normal rats to the level observed in kininogen-deficient rats, but had no effect on the hypotension caused by LPS in kininogen-deficient rats. 4. TCV309 (0.1 mg kg-1, i.v.) selectively inhibited the hypotension caused by repetitive injection of PAF for up to 180 min. Pretreatment with TCV309 caused a near complete inhibition of the LPS-induced hypotension in kininogen-deficient and normal B/N rats. 5. In the normal rats, dexamethasone (0.5 mg kg-1, i.p.) inhibited the second phase of the hypotension induced by LPS, but not the first phase of the hypotension. 6. A small amount of BK (0.1 nmol kg-1) potentiated the hypotensive action of PAF (0.01 microg kg-1),when they were injected simultaneously.7. In conclusion, we demonstrate that formation of endogenous BK contributes primarily to the acute,but not to the delayed hypotension afforded by endotoxin in the rat. In contrast, formation of endogenous PAF contributes to both the acute and the delayed hypotension afforded by endotoxin in vivo.

Topics: Amino Acid Sequence; Animals; Bradykinin; Dose-Response Relationship, Drug; Endotoxins; Hypotension; Isoquinolines; Kininogens; Lipopolysaccharides; Male; Molecular Sequence Data; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Inbred BN; Rats, Mutant Strains; Rats, Sprague-Dawley; Reference Values; Tetrahydroisoquinolines

The aim of the present study was to investigate the role of bradykinin as well as that of platelet-activating factor in the endotoxin-induced acute vascular permeability increase in the dorsal skin of rats by use of kininogen-deficient and normal Brown-Norway rats. In the kininogen-deficient rats, the dose-dependent dye exudation induced by endotoxin was about one half of that in the normal rats at any doses of endotoxin tested (0.1-1.0 mg per site), whereas the dose-response curves obtained by bradykinin (1-100 nmol per site), platelet-activating factor (0.1-1 nmol per site) or histamine (50-500 nmol per site) were the same in both rats. This effect induced by endotoxin in the kininogen-deficient rats was not changed by pretreatment with a bradykinin B2 receptor antagonist, HOE140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin, 1 mg kg-1 i.v.), whereas the endotoxin-induced response in the normal rats was attenuated by the receptor antagonist. These responses in both kininogen-deficient and normal rats were significantly inhibited by a selective platelet-activating factor antagonist, TCV309 (3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4,-tetrahydro-2- isoquinolylcarbonyl-oxy)-ethyl]-carbamoyl]-ethyl]carbamoyl]-1-prop yl- pyridinium nitrate, 0.1 mg kg-1 i.v.). These results suggest that bradykinin could be one of the major mediators in the endotoxin-induced vascular permeability increase in rat skin in addition to platelet-activating factor.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Dose-Response Relationship, Drug; Endotoxins; Escherichia coli; Isoquinolines; Kininogens; Lipopolysaccharides; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Pyridinium Compounds; Rats; Rats, Inbred BN; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Regional Blood Flow; Skin; Tetrahydroisoquinolines