Mechanisms underlying the relaxation response induced by bradykinin in the epithelium‐intact guinea‐pig trachea in vitro

Abstract

1 In this study, we investigated some of the signalling pathways involved in bradykinin (BK)-induced relaxation in epithelium-intact strips of the guinea-pig trachea (GPT þ E). BK induced timeand concentration-dependent relaxation of GPT þ E. Similar responses were observed for prostaglandin E 2 (PGE 2 ) or the combination of subthreshold concentrations of BK plus PGE 2 . 2 The nonselective cyclooxygenase (COX) inhibitors indomethacin or pyroxicam, or the selective COX-2 inhibitors DFU, NS 398 or rofecoxib, but not the selective COX-1 inhibitor SC 560, all abolished BK-induced relaxation. 3 The tyrosine kinase inhibitors herbimycin A and AG 490 also abolished BK-induced relaxation in GPT þ E. 4 The nonselective nitric oxide synthase (NOS) inhibitor 7-NINA concentration-dependently inhibited BK effects. 5 BK-induced relaxation was prevented by the selective antagonists for EP 3 (L 826266), but not by EP 1 (SC 19221), EP 1 /EP 2 (AH 6809) or EP 4 (L 161982) receptor antagonists. 6 Otherwise, the selective inhibitors of protein kinases A, G and C, mitogen-activated protein kinases, phospholipases C and A 2 , nuclear factor-kB or potassium channels all failed to significantly interfere with BK-mediated relaxation. 7 BK caused a marked increase in PGE 2 levels, an effect that was prevented by NS 398, HOE 140 or AG 490. 8 COX-2 expression did not differ in preparations with or without epithelium, and it was not changed by BK stimulation. However, incubation with BK significantly increased the endothelial NOS (eNOS) and neuronal NOS (nNOS) expression, independent of the epithelium integrity. 9 Our results indicate that BK-induced relaxation in GPT þ E depends on prostanoids (probably PGE 2 acting via EP 3 receptors) and NO release and seems to involve complex interactions between kinin B 2 receptors, COX-2, nNOS, eNOS and tyrosine kinases.

Role of Cyclooxygenase Isoforms and Nitric-Oxide Synthase in the Modulation of Tracheal Motor Responsiveness in Normal and Antigen-Sensitized Guinea Pigs

“…Although various authors reported the absence of COX-2 expression in the tracheobronchial system of normal guinea pigs (Amann et al, 2001;Oguma et al, 2002), the role of COX-2 has been proposed to be relevant in the regulation of tracheal intrinsic tone in this species (Charette et al, 1995), and a constitutive COX-2 expression has been reported in normal airways (Schlemper et al, 2005). Our results from normal guinea pigs, showing that DFU enhances histamineinduced contraction, indicate a functional role for COX-2 isoform that seems to mediate an inhibitory control on airway muscle.…”

Insulin causes airway hyper-reactivity

“…Conclusions: Insulin has acute contractile effects on guinea pig airways, which were significantly inhibited by prostaglandin synthesis inhibitor indomethacin confirming the involvement of contractile prostaglandins in insulin-induced airwayinflammatory drug, which inhibits cyclooxygenase enzyme that participate in prostaglandin synthesis from arachidonic acid. 7 It is well-established from the review of literature that insulin-induced isolated tracheal muscle contraction in guinea pig model described in the present study closely resembles the bronchoconstriction induced by pulmonary delivery of inhaled insulin as high concentration of insulin gets deposited in airway smooth muscle compartment in both cases. 8 Aim of our study was to explore the magnitude of insulin-induced airway hyper-reactivity and to evaluate the potential role of prostaglandins in insulin-mediated tracheal tissue contraction of guinea pig in vitro.…”

Bradykinin Contracts Rat Urinary Bladder Largely Independently of Phospholipase C

“…Therefore, these data demonstrate that not only M 3 muscarinic but also bradykinin receptors cause bladder contraction in a largely PLC-independent manner. Of note, the recent data on PLCinvolvement in P2Y6 receptor-mediated bladder contraction relied on a high concentration of U 73,122 (50 mM) and did not include a negative control (Yu et al, 2013).Work in guinea pig trachea also supports the idea that bradykinin-induced smooth muscle contraction may occur independently of PLC (Schlemper et al, 2005). Therefore, additional experiments were designed to explore which other signaling pathways may be involved in bradykinin-induced bladder contraction.…”