Time‐dependent synergistic interactions between the vasodilator neuropeptide, calcitonin gene‐related peptide (CGRP) and mediators of inflammation

1 The effect of pretreatment with bacterial endotoxin (LPS, 10 pg, i.v., 24 h) on the bradykinin B1 and B2 receptor-induced oedema in the rat paw, and the interaction of B,-mediated responses with other inflammatory mediators, was investigated. 2 Intraplantar (i.pl.) injection of the selective B1 agonist, des-Arg9-BK (DABK, 100 nmol) in naive animals pretreated with the angiotensin converting enzyme inhibitor, captopril caused a small increase in paw volume (0.04 + 0.003 ml, mean + s.e.mean, n = 6), while the B2-selective agonist, tyrosine8-bradykinin (T-BK, 3 nmol) induced marked oedema (0.36 + 0.02 ml). However, i.pl. injection of DABK (3-300 nmol) in rats pretreated with LPS (24 h beforehand) resulted in a marked dose-and time-related increase in paw volume, with mean ED50 of 24.1 nmol. In contrast, oedema caused by T-BK (3 nmol) was reduced by 79 + 4% in animals treated with LPS when compared with naive animals. 3 Oedema caused by prostaglandin E2 (PGE2, 10 nmol) was unaffected by LPS treatment, while oedema induced by histamine (100 nmol), 5-hydroxytryptamine (5-HT, 10 nmol) and substance P (SP, 3 nmol) was reduced (P<0.05).4 The selective B, antagonist, des-Arg9[Leu8]-BK (100-300 nmol), produced dose-dependent inhibition of DABK (100 nmol)-induced paw oedema in LPS-treated animals with mean IC50 of 134 nmol, while the selective B2 antagonists, Hoe 140 and NPC 17731 (each 10 nmol), had no effect.5 Treatment of animals with dexamethasone (0.5 mg kg-', s.c.) 24 or 48 h prior to LPS injection resulted in a graded inhibition of DABK (100 nmol)-induced oedema formation (58+3 and 82+2%, respectively), and almost reversed to control value oedema formation induced by T-BK (3 nmol) in LPSpretreated rats. Cycloheximide (1 mg kg-1, s.c.) or indomethacin (2 mg kg-1, i.p.) pretreatment 24 and 1 h prior to LPS injection, respectively, markedly inhibited DABK (100 nmol)-induced paw oedema (98+2 and 50+4%, respectively). 6 Intraplantar injection of submaximal dose of DABK (10 nmol) in LPS-treated rats produced modest paw oedema (0.09+0.03 ml). However, i.pl. injections of PGE2, prostacyclin (PGI2), calcitonin-generelated peptide (CGRP), SP, 5-HT, or platelet activating factor (PAF) (each 1 nmol), which alone caused little or no paw oedema, resulted in a potentiation of the DABK-induced oedema. The increases in paw volume (in ml) were: PGE2 + DABK (0.31 + 0.03), PG12 + DABK (0.39 + 0.02), CGRP + DABK (0.35+0.04), DABK+SP (0.33+0.04), DABK+5-HT (0.40+0.02) and DABK+PAF (0.38+0.016) ml. In contrast, histamine (1 nmol) was ineffective in potentiating the response to DABK. 7 The selective B1 receptor antagonist, DALBK (100-300 nmol), produced dose-dependent inhibition of paw oedema potentiation induced by co-injection of DABK and other mediators with mean ID50s (nmol) of: 180, 160, 139 and 135 in the presence of PGE2, PGI2, SP and 5-HT, respectively.

Section: Discussionsupporting

confidence: 83%

Upregulation of B₁ receptor mediating des‐Arg₉‐BK‐induced rat paw oedema by systemic treatment with bacterial endotoxin

Campos

Souza

Calixto

1996

“…Several studies have suggested a pro-inflammatory activity for CGRP (Gamse & Saria, 1985;Buckley et al, 1991;1992). However, in our model CGRP837 was unable to inhibit the TDI-induced tracheal hyperreactivity and the cutaneous responses.…”

Section: Discussioncontrasting

confidence: 69%

“…The tachykinins have been shown to induce proliferation of mitogenstimulated T-lymphocytes (Payan et al, 1983;Stanisz et al, 1986;Casini et al, 1989), migration of leukocytes (Marasco et al, 1981;Moore, 1984), and activation of macrophages (Koff & Dunegan, 1985). In contrast, CGRP has been found to inhibit the proliferation of mitogen-stimulated T-lymphocytes (Umeda et al, 1988;Casini et al, 1989), although several studies also suggest that CGRP may be pro-inflammatory on its own (Gamse & Saria, 1985;Buckley et al, 1991;1992). In the literature the role for sensory neuropeptides in the induction of airway hyperreactivity has been investigated in several studies (Boichot et al, 1995;Sakamoto et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

The involvement of sensory neuropeptides in toluene diisocyanate‐induced tracheal hyperreactivity in the mouse airways

Scheerens

Buckley

Muis

et al. 1996

1 Recently, we developed a murine model to investigate toluene diisocyanate (TDI)-induced occupational asthma. After skin-sensitization and intranasal challenge with TDI (1%) mice exhibited tracheal hyperreactivity 24 h after the challenge. 2 The aim of the present study was to investigate the possible role for sensory neuropeptides in the development of this tracheal hyperreactivity. 3 First, we demonstrated that direct application of TDI in vitro induced the release of tachykinins from the sensory nerves in the mouse isolated trachea. Second, capsaicin pretreatment, resulting in the depletion of sensory neuropeptides, completely abolished the TDI-induced tracheal hyperreactivity 24 h after the challenge. Third, the selective neurokinin, (NK1)-receptor antagonist RP 67580 (0.2 Mumol kg-') also inhibited tracheal hyperreactivity when it was administered before the challenge. However, administration of RP 67580 during the sensitization phase did not result in a suppression of the TDIinduced tracheal hyperreactivity 24 after the challenge. 4 When TDI-sensitized mice were topically challenged with TDI a marked ear swelling response was observed. The cutaneous response after TDI application was not affected by capsaicin pretreatment or RP 67580 administration. 5 These results clearly show that sensory neuropeptides, particularly tachykinins, are essential for the development of TDI-induced tracheal hyperreactivity during the effector phase. The differences between the airways and skin with respect to the sensory neuropeptides is intriguing and could suggest a local action for the tachykinins in the airways.

“…In addition, kinins may also stimulate visceral sensory neurones to release pro-inflammatory neuropeptides such as substance P (SP), neurokinin A or calcitonin gene-relatedpeptide (CGRP) (Bhoola et al, 1992; for review see: Farmer & Burch, 1992;Geppetti, 1993). Therefore, a large part of the pro-inflammatory and algesic actions of kinins is most likely to be due to synergistic actions between these mediators (Brain & Williams, 1989;Buckley et al, 1991;Cruwys et al, 1992;Warren et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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

Campos

Calixto

1995

113

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.