Effects of epithelium removal on relaxation of airway smooth muscle induced by vasoactive intestinal peptide and electrical field stimulation

Abstract

1 We have studied the effect of epithelium removal on relaxation of guinea-pig isolated tracheal smooth muscle induced by vasoactive intestinal peptide (VIP) or stimulation of non-adrenergic, non-cholinergic (NANC) inhibitory nerves. Also examined were the effects of inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE).2 Epithelium removal produced a 3.6 + 0.4 fold leftward shift in the VIP concentration-response curve. The supersensitivity to VIP, following epithelium removal was abolished by phosphoramidon or thiorphan (NEP inhibitors), but unaffected by captopril (an ACE inhibitor). In intact trachea, the NEP inhibitors produced leftward shifts in the VIP curves similar to those produced by epithelium removal.3 In contrast to responses to exogenous VIP, neurogenic NANC inhibitory responses to electrical field stimulation were affected neither by epithelial denudation nor by the peptidase inhibitors. 4 As in previous studies, epithelium removal increased tracheal sensitivity to isoprenaline. This was not altered by pretreatment with a cocktail of peptidase inhibitors. Thus, the effect of the NEP inhibitors on responses to VIP appears to be relatively specific. 5 These data indicate that exogenous VIP is a substrate for airway NEP, since inhibition of the enzyme potentiates the peptide. This is further evidence that the airway epithelium provides a source for the metabolism of mediators.6 In guinea-pig trachea the NEP responsible for cleaving VIP may be located largely in the epithelial layer, since NEP inhibition was without effect on sensitivity to VIP in epithelium-denuded preparations. If VIP is a NANC inhibitory neurotransmitter in this tissue, its degradation endogenously does not appear to involve epithelial NEP.

The respiratory epithelium and airway smooth muscle homeostasis: its relevance to asthma

“…Similar inter-and intra-species heterogeneity has also been observed for other relaxant agonists such as adenosinc [26,27] and methylxanthines such as theophyllinc [28.29]. In some animal species epithelium removal also enhances tracheal smooth muscle sensitivity to relaxation induced by vasoactive intestinal peptide (VIP) [30].…”

Dual bronchodilatory and pulmonary anti‐inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors

“…This is likely to be due to the enhanced stability of RO5024118 to neutral endopeptidase release from the epithelium of these isolated tissues. Other studies have shown that decreasing the neutral endopeptidase activity in isolated airway tissues by treating with inhibitors or removing the epithelium leads to enhanced VIP‐induced relaxation (Farmer and Togo, 1990; Tam et al ., 1990; Groneberg et al ., 2001).…”

VIP antagonists enhance excitatory cholinergic neurotransmission in the human airway

“…VIP is also inactivated by epithelial neutral endopeptidase (NEP) [5] or by mast cell chymase and tryptase [32]. Recently, it was demonstrated that VIPinduced airway relaxation is enhanced by peptidase inhibitors in the epitheliumdenuded airway [10].…”