Proinflammatory characteristics of a nonpeptide bradykinin mimic, FR190997, in vivo.
1. Proinflammatory potency of the nonpeptide bradykinin (BK) B(2) receptor agonist FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline) was investigated. 2. Intradermal injection of FR190997 (0.03 - 3 nmol site(-1)) into dorsal skin of rats increased vascular permeability in a dose-dependent manner. The effect was less than that of BK, but it was long-acting and was inhibited by treatment with FR173657 (3 mg kg(-1), p.o.). Captopril (10 mg kg(-1), i.p.) did not enhance the plasma extravasation by FR190997 (0.3 nmol site(-1)) in the presence of soybean trypsin inhibitor (SBTI, 30 microg site(-1)). 3. Subcutaneous injection of FR190997 (3 nmol site(-1)) into the hindpaw of mice markedly induced paw swelling. The oedema lasted up to 3 h after the injection. Administration of indomethacin or NS-398 (10 mg kg(-1), i.p.) significantly reduced it at 3 h after the injection. 4. Simultaneous i.p. injection of prostaglandin (PG) E(2) (1 nmol site(-1)) or beraprost sodium (0.5 nmol site(-1)) with FR190997 (5 nmol site(-1)) greatly enhanced frequency of writhing reactions in mice. 5. FR190997 (0.3 - 30 nmol kg(-1), i.v.) showed less increase in airway opening pressure (Pao) in the guinea-pig after i.v. injection. Furthermore, FR190997 (0.03 - 30 nmol) resulted in a very weak contraction of tracheal ring strips and lung parenchymal sections in vitro. 6. In mice sponge implants, topical application of FR190997 increased angiogenesis and granulation with enhanced expressions of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) mRNAs. 7. These results indicate that FR190997 has proinflammatory long-lasting characteristics and it might be 'a stable tool' for studying the role of BK B(2) receptor in vivo.
Hayashi
I
I
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara-shi, Kanagawa 228-8555, Japan. hayashii@med.kitasato-u.ac.jp
Ishihara
K
K
Kumagai
Y
Y
Majima
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced; D006168:Guinea Pigs; D007249:Inflammation / Q000139:chemically induced; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; C105311:FR 173657; C107104:FR 190997; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D002216:Captopril; D001920:Bradykinin