fr-173657 and Edema

1. The involvement of bradykinin (BK) B(2) receptor in acute pancreatitis induced by pancreaticobiliary duct ligation was investigated in rats. 2. The activities of amylase and lipase in the serum, the water content of the pancreas, and vacuolization of the acinar cells were significantly increased 2 h after obstruction of the duct in Sprague-Dawley rats. 3. Elevated serum amylase activity, increased pancreatic oedema, and damage of the pancreatic tissue were significantly less marked in plasma kininogen-deficient, B/N-Katholiek rats than in the normal strain, B/N-Kitasato rats 2 h after the ligation. 4. Obstruction of the pancreaticobiliary duct augmented the level of (1-5)-BK (Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)), a stable BK metabolite, in the blood from 73.0+/-21.7 pg ml(-1) at 0 h to 149.8+/-38.0 pg ml(-1) at 2 h after the induction of pancreatitis in SD rats. 5. Administration of a BK B(2) receptor antagonist, FR173657 (100 mg kg(-1), p.o.) or Hoe140 (100 nmol kg(-1), s.c.), reduced the elevation of amylase and lipase activities in the serum and of pancreatic water content in a dose-dependent manner. The effective attenuation of oedema formation and vacuolization by the antagonists was also confirmed light-microscopically. In contrast, treatment with gabexate mesilate or indomethacin did not cause significant suppression of the pancreatitis. 6. These findings suggest a possible involvement of kinin B(2) receptor in the present pancreatitis model. Furthermore, they point to the potential usefulness of the B(2) receptor in clinical acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bile Ducts; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Edema; Kininogens; Lipase; Male; Pancreas; Pancreatic Ducts; Pancreatitis; Peptide Fragments; Quinolines; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Water

Inflammatory pain was induced following an intradermal injection of carrageenin into rat paws, and the hyperalgesia was measured in terms of withdrawal time following thermal pain stimulation of the inflamed paw. This hyperalgesia was significantly less in kininogen-deficient Brown Norway (B/N)-Katholiek rats, which also showed less swelling in carrageenin-induced paw edema, than in normal B/N-Kitasato rats at 1 approximately 4 hr after the carrageenin injection (at the early phase). However, 24 hr after the injection, hyperalgesia and the swelling volume of the kininogen-deficient rats were almost the same as those in normal rats. The bradykinin B2 receptor antagonist FR173657, (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide, attenuated the carrageenin-induced swelling and hyperalgesia of the normal rats at the early phase to almost the levels of the B/N-Katholiek rats. Pretreatment with indomethacin, a cyclooxygenase inhibitor, also inhibited the carrageenin-induced responses significantly in normal rats. These results indicate that bradykinin, acting on the B2 receptor, is the main mediator at the early phase of inflammatory pain of carrageenin edema and that prostaglandins, produced by cyclooxygenase, potentiate the effects of bradykinin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Disease Models, Animal; Edema; Female; Indomethacin; Kininogens; Male; Pain; Quinolines; Rats

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Capillary Permeability; Captopril; Edema; Guinea Pigs; Inflammation; Lung; Male; Mice; Mice, Inbred ICR; Molecular Mimicry; Neovascularization, Pathologic; Quinolines; Rats; Receptor, Bradykinin B2; Receptors, Bradykinin; Reverse Transcriptase Polymerase Chain Reaction; Trachea

Biological actions of a novel non-peptide B2 receptor agonist, FR190997, were examined by comparing them with those of bradykinin. The paw edema was induced by subcutaneous injection of 30 microl of solution of bradykinin (0.3, 0.6, and 1.2 nmol) or FR190997 (0.1, 0.3, and 0.9 nmol) into the right hind paw of ICR male mice. Bradykinin caused a dose-dependent edema formation, which peaked at 15 min and ceased after 150 min. FR190997 also formed a dose-dependent edema, peaking at 15-30 min with a slight delay compared to bradykinin and this response continued over 200 min. The edema formed by bradykinin or FR190997 was inhibited by pretreatment with HOE140 (1 mg/kg) injected intraperitoneally 30 min before the injection of each agonist. A novel non-peptide B2 antagonist, FR173657 (30 mg/kg, i.p. 30 min before the agonist), also diminished these responses by bradykinin and FR190997 dose-dependently. Indomethacin (10 mg/kg, i.p. 30 min before) inhibited the response to FR190997, suggesting that release of prostaglandins induced by the B2 agonistic action might be involved in this inflammatory process induced by FR190997. The hypotensive action of FR190997 was also examined. Intravenously injected FR190997 caused the systemic hypotensive response in Sprague-Dawley male rats anesthetized with pentobarbital. The potency of FR190997 was weaker than that of bradykinin, when compared with the maximal hypotension. Duration of the hypotensive response of FR190997 was significantly longer than that of bradykinin. These results indicate that FR190997 has the B2 agonistic action similar to bradykinin and is also a good tool for in vivo examination of the B2 receptor.

Topics: Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Edema; Hindlimb; Hypotension; Male; Mice; Mice, Inbred ICR; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin

A novel non-peptide bradykinin B2-receptor agonist, FR190997 (8-[2,6-dichloro-3-[N-[(E)4-(N-methylcarbamoyl)cinnamidoacetyl+ ++]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinolin e), induced dose-dependent and longer-lasting swelling than bradykinin in the mouse paw. The swelling, peaking around 30 min, was suppressed dose-dependently by intraperitoneal administration of FR173657, a novel non-peptide B2-receptor antagonist. A known B2-antagonist, Hoe 140, also significantly suppressed this edema. The result indicates that the novel B2-agonist FR190997, being more stable than bradykinin, could induce plasma exudation locally in mice via the B2-receptor as a substitute for bradykinin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Edema; Foot; Hindlimb; Male; Mice; Mice, Inbred ICR; Quinolines; Receptors, Bradykinin

1. Kinins are believed to play a key role in many inflammatory conditions. Therefore, bradykinin antagonists are being developed for potential therapeutic applications. In the present investigation we describe the pharmacology, in vivo, of (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[2-methyl-8-quinoliny l) oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657), a novel, non-peptide bradykinin antagonist. 2. The hypotensive effects of i.v. injections of bradykinin (50 pmol) in captopril-pre-treated anaesthetized rats were significantly inhibited by 100 nmol kg-1 FR173657 s.c., and completely abolished by 300 nmol kg-1. The full inhibitory effect developed within 60 min and remained unchanged for at least 4 h. However, the effect was reversible, since 24 h after an injection of 300 nmol kg-1 FR173657 no inhibitory effect could be observed. 3. The plasma protein extravasation into the pancreas and duodenum induced by an i.v. infusion of bradykinin (11 nmol kg-1 within 20 min) in captopril-treated anaesthetized rats was completely abolished by FR173657 at doses of 30 nmol kg-1 s.c. and above, given 60 min before bradykinin. FR173657 3 nmol kg-1 was ineffective, while a dose of 10 nmol kg-1 produced an intermediate effect. 4. The paw oedema induced by the subplantar injection of bradykinin (30 nmol) in anaesthetized rats was inhibited slightly by s.c. injection of FR173657 0.3 mumol kg-1, whereas 1 and 3 mumol kg-1 produced significant inhibition of the bradykinin-induced oedema. The maximum inhibition amounted to about 50% and could not be increased even when the dose of FR173657 was increased to 30 mumol kg-1. FR173657 did not effect the oedema caused by histamine or 5-hydroxytryptamine. 5. Bradykinin (20 nmol kg-1, i.v.) caused increases in pulmonary inflation pressure by 300-600 Pa in anaesthetized, respirated guinea-pigs. The effect was reduced to 58 +/- 9% of the initial value 60 min after the s.c. injection of FR173657 1 mumol kg-1, whereas only 9 +/- 7% remained after 10 mumol kg-1. The bronchoconstrictor actions of histamine remained unaffected by FR173657. 6. In summary, FR173657 is a highly potent and selective bradykinin antagonist. The inhibitory action in vivo lasts for longer than 4 h but is fully reversible. FR173657, or similar compounds, will be a useful tool for the pharmacological investigation of pathophysiological states and may possess a therapeutic potential in diseases involving the endogenous release of kinins.

Topics: Animals; Blood Proteins; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Edema; Female; Guinea Pigs; Hypotension; Male; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2