Differential sensitivity of antinociceptive assays to the bradykinin antagonist Hoe 140

1 The e ects of a novel, potent and orally active nonpeptide bradykinin B 2 receptor antagonist, FR167344 (N -[N -[3 -[(3 -bromo-2 -methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2,4-dichlorophenyl]-Nmethylaminocarbonylmethyl]-4-(dimethylaminocarbonyl) cinnamylamide hydrochloride) were tested in three di erent in vivo models of in¯ammation. 2 Oral administration of FR167344 inhibited carrageenin-induced paw oedema in rats (carrageenin: 1%, 0.1 ml per animal, intraplantar), with an ID 50 of 2.7 mg kg 71 at 2 h after carrageenin injection (n=10 or 11). 3 Oral administration of the compound also inhibited kaolin-induced writhing (kaolin: 250 mg kg 71 , i.p.) in mice, with ID 50 of 2.8 mg kg 71 in 10 min writhing and 4.2 mg kg 71 in 15 min writhing (n=19 or 20). 4 Additionally, oral administration of FR167344 inhibited caerulein-induced pancreatic oedema with an ID 50 of 13.8 mg kg 71 as well as increases in amylase and lipase of blood samples with ID 50 of 10.3 and 7.4 mg kg 71 , respectively, in rats (n=10). 5 These results show that FR167344 is an orally active, anti-in¯ammatory and anti-nociceptive agent in carrageenin-induced paw oedema, kaolin-induced writhing and caerulein-induced pancreatitis. FR167344 may have therapeutic potential against in¯ammatory diseases by oral administration and it may be a useful tool for studying the involvement of B 2 receptors in various in vivo models of in¯ammation.

Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 63%

Effects of a nonpeptide bradykinin B₂ receptor antagonist, FR167344, on different in vivo animal models of inflammation

Asano¹,

Hatori²,

Inamura³

et al. 1997

“…In addition, prior treatment of animals with dexamethasone (0.5 mg kg-', 24 h previously) also consistently antagonized DABK (100 nmol/paw)-induced oedema in desensitized paws (53 ± 4% inhibition) (P <0.05) (Figure 9a). In contrast, the same treatment with dexamethasone had no effect on oedema induced by BK (3 nmol/paw) in naive paws (Figure 9b Similar inhibition of kinin responses in vivo by these B2 antagonists has been reported (Wirth et al, 1991;Dray et al, 1992;Correa & Calixto, 1993;Heapy et al, 1993;. It is important to mention that co-injections of different combinations of PGE2, PGI2, SP, CGRP or histamine always resulted in oedema that was smaller than that caused by any co-injections with BK.…”

Section: Introductionsupporting

confidence: 66%

Involvement of B₁ and B₂ receptors in bradykinin‐induced rat paw oedema

Campos

Calixto

1995

114

1 The mechanisms involved in bradykinin (BK)-induced oedema in the rat paw as well as the interactions between BK and several inflammatory mediators, have been investigated. 2 Intraplantar injection of BK (1 nmol/paw) in rats pretreated with captopril (5 mg kg-', s.c.) caused a small amount of oedema formation (0.17 ± 0.05 ml). Des-Arg9-BK (DABK, a selective B, receptor agonist) up to 300 nmol/paw caused minimal oedema (0.03 ± 0.01 ml). 3 Co-administration of prostaglandin E2 (PGE2), prostaglandin 12 (PGI2), calcitonin gene-related peptide (CGRP), 5-hydroxytryptamine (5-HT), substance P (SP) or platelet activating factor (PAF) (1 pmol-1 nmol/paw) with BK (1 nmol/paw) dose-dependently potentiated BK-induced paw oedema.The rank order of potency (mean EDm, pmol/paw) for this effect was: SP (8.1)>PAF (13.7)>PGI2 (DALBK, up to 300 nmol/paw) had no effect. 5 Daily intraplantar injections of BK (10 nmol/paw) once a day for 7 consecutive days caused a progressive and complete desensitization of the paw oedema, which was specific for BK, since paw oedema induced by PAF, PGE2, SP or histamine was not affected. In addition, the oedema caused by BK in the paw desensitized to the peptide was almost completely reversed if BK was co-injected with PGE2, PGI2 or SP (1 nmol/paw). Injection of PGE2 or SP (10 nmol/paw) together with the first BK injection (1O nmol/paw), partially prevented BK-induced desensitization. 6 When animals were completely desensitized to BK, DABK (100nmol/paw) caused paw oedema (0.25 ± 0.03 ml) which was consistently blocked by the B, receptor antagonist, DALBK (100 nmol/ paw).7 Treatment of animals with dexamethasone (0.5 mg kg-', s.c., 24 h previously) antagonized paw oedema induced by DABK (100 nmol/paw) in desensitized paws, but not that induced by BK (3 nmol/ paw) in naive paws. The steroid also prevented the recovery of oedema seen after co-injection of BK with PGE2 or PGI2 (1 nmol/paw) in desensitized paws. 8 These results suggest that both B, and B2 receptors are involved in BK-induced rat paw oedema. The B2 receptors are constitutive, but induction of expression of B, receptors seems to occur only after complete desensitization of the paw to BK. In addition, very low doses of inflammatory mediators markedly potentiate BK-induced paw oedema and can attenuate BK-induced paw oedema desensitization. Such mechanisms may be relevant for the manifestation of acute and chronic inflammatory processes.

“…Both PKSI-527 and SBTI, a speci®c and non-speci®c plasma kallikrein inhibitors, respectively, also reduced the mouse writhing response indicating involvement of the kallikrein ± kinin system (KKS), in agreement with other studies (Steranka et al, 1987;Chau et al, 1991;Heapy et al, 1993). In addition, the BK B 2 receptor antagonist HOE-140 reduced the acetic acid-induced writhes, con®rming other reports (Steranka et al, 1987;Heapy et al, 1993).…”

Section: Discussionsupporting

confidence: 90%

“…In addition, the BK B 2 receptor antagonist HOE-140 reduced the acetic acid-induced writhes, con®rming other reports (Steranka et al, 1987;Heapy et al, 1993). These data indicated activation of both tissue and plasma kinin releasing pathways in the mouse writhing response.…”

Section: Discussionsupporting

confidence: 88%

Evidence for activation of the tissue kallikrein‐kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor

Emim¹,

Souccar²,

Castro³

et al. 2000

1 The pharmacological activity of phenylacetyl-Phe-Ser-Arg-N-(2,4-dinitrophenyl)-ethylenediamine (TKI), a tissue kallikrein speci®c inhibitor, was assessed using models of nociception and in¯ammation in mice. 2 Injection of TKI (13.6 ± 136 mmol kg 71 , i.p. or 41 ± 410 mmol kg 71 , s.c.) produced a dose-related inhibition of the acetic acid-induced writhes (by 37 to 85% or 34 to 80%, respectively). The antinociceptive activity of TKI (41 mmol kg 71 , i.p.) was maximal after 30 min injection and lasted for 120 min. The e ect was unaltered by pretreatment with naloxone (8.2 mmol kg 71 , s.c.) or bilateral adrenalectomy. 3 TKI (41 and 136 mmol kg 71 , i.p.) produced a dose-related decrease of the late phase of formalininduced nociception by 79 and 98%, respectively. At 136 mmol kg 71 , i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 mmol kg 71 , i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%). 4 TKI (41 mmol kg 71 , i.p. or 410 mmol kg 71 , s.c.) reduced the oedematogenic response, from the second to the ®fth hour after carrageenin injection by 36 to 30% or by 47 to 39%, respectively. 5 Pretreatment with TKI (41 mmol kg 71 , i.p.) reduced the capsaicin-induced neurogenic in¯ammation in the mouse ear by 54%. 6 It is concluded that TKI presents antinociceptive and antiin¯ammatory activities mediated by inhibition of kinin formation by tissue kallikrein in mice. The results also indicate that the tissue kallikrein-dependent pathway contributes to kinin generation in nociceptive and in¯ammatory processes in mice.