Modulation of ET‐1‐induced contraction of human bronchi by airway epithelium‐dependent nitric oxide release via ET_A receptor activation

Abstract

1 The purpose of this work was to investigate whether endothelin-1 (ET-1) was able to induce the release of an inhibitory factor from the airway epithelium in isolated human bronchi and to identify this mediator as well as the endothelin receptor involved in this phenomenon. 2 In intact bronchi, ET-1 induced a concentration-dependent contraction (7logEC 50 =7.92+0.09, n=18) which was potentiated by epithelium removal (7logEC 50 =8.65+0.11, n=17). BQ-123 , an ET A receptor antagonist, induced a signi®cant leftward shift of the ET-1 concentration-response curve (CRC). This leftward shift was abolished after epithelium removal. 3 L-NAME (3610 73 M), an inhibitor of nitric oxide (NO) synthase, induced a signi®cant leftward shift of the ET-1 CRC, and abolished the potentiation by BQ-123 (10 78 M) of ET-1-induced contraction. 4 In intact preparations, the ET B receptor antagonist BQ-788 induced only at 10 75 M a slight rightward shift of the ET-1 CRC. In contrast, in epithelium-denuded bronchi or in intact preparations in the presence of L-NAME, BQ-788 displayed a non-competitive antagonism toward ET-1-induced contraction. 5 IRL 1620, a selective ET B receptor agonist, induced a contraction of the isolated bronchus (7logEC 50 =7.94+0.11, n=19). This e ect was not modi®ed by epithelium removal or by BQ-123. BQ-788 exerted a competitive antagonism against IRL 1620 which was similar in the presence or absence of epithelium. 6 These results show that ET-1 exerts two opposite e ects on the human airway smooth muscle. One is contractile via ET B -receptor activation, the other is inhibitory and responsible of NO release which counteracts via ET A -receptor activation the contraction.

Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury

“…Additionally, ET-1, through interaction with both ET A and ET B receptors, is a mediator of airway tone. ET-1 binding to the ET B receptor promotes bronchial smooth muscle cell contraction, whereas interaction with the ET A receptor promotes NO-induced relaxation [40]. Although ET-1 has been shown to modulate the expression of NO, Markewitz et al [41], using an vitro assay, showed that ET-1, through the ET A receptor pathway, inhibited the activity (approx.…”

In vitro sensitization of human bronchus by β2-adrenergic agonists

“…Studies in animal and human airways have shown that the epithelial ET A receptor may mediate NO production (via the constitutive NOS) and prostaglandin E 2 production (via the epithelial COX-2) (3,8,31,44). Epithelial NO and prostaglandin E 2 are relaxant for the airway smooth muscle.…”

“…Epithelial NO and prostaglandin E 2 are relaxant for the airway smooth muscle. In a recent study, Naline and colleagues (44) found that NO is the major determinant of the epithelial regulation of the human airway smooth muscle contraction to ET-1. Our results are in agreement with these authors, because we showed that L-NAME, but not indomethacin and GR-32191, enhanced the contractility to ET-1.…”

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

“…Both ET A and ET B receptors are present on smooth muscle cells of the airways and mediate strong contractions. ET B receptors are present on the airway epithelium as well, where they can induce relaxation through the release of nitric oxide [25] . Asthmatic inflammation causes disruption of the epithelium [26] , which decreases the dilation mediated by ET B receptors.…”