Pituitary adenylate cyclase-activating peptide (PACAP) 38 displays several biological activities relevant to obstructive airway disease.In this study, the occurrence of PACAP 38 in human small bronchi and corresponding pulmonary arteries was analysed immunocytochemically. The dilatory effects of this peptide on the same structures were also studied in vitro.A moderate number of PACAP-like immunoreactive nerve fibres was seen in association with bronchial and vascular smooth muscle and around seromucous glands. PACAP 38 caused a concentration-dependent relaxation of precontracted bronchial and pulmonary arterial segments. The maximal relaxation was more pronounced in the airways than in the arteries, whereas the potency in both was identical. PACAP 38 caused relaxation of all segments tested (nine patients), whereas vasoactive intestinal polypeptide (VIP) failed to cause relaxation of bronchial segments from six of nine patients. Both PACAP and VIP dilated all pulmonary arterial segments tested.In conclusion, pituitary adenylate cyclase-activating peptide 38 is a potent dilator of human bronchi and is present in the human lung. Pituitary adenylate cyclaseactivating peptide 38 may, therefore, play a role in the endogenous regulation of airway tone. The inhibitory effects of pituitary adenylate cyclase-activating peptide 38 are more consistent than those of the related neuropeptide vasoactive intestinal polypeptide, perhaps reflecting a difference in susceptibility to degrading enzymes. Eur Respir J 2000; 15: 243±247.

Culture of tracheal segments appears to be a suitable assay for the examination of long-term effects induced by inflammatory mediators on neurally mediated airway contractions. NGF treatment enhanced the cholinergic, nerve-dependent contractions and increased the amount of nerve fibres seen in the murine tracheal segments, suggesting a role for NGF in the development of airway hyper-responsiveness.

These results imply that PACAP is an important endogenous mediator in human upper airways, with a potential role as a regulator of vascular smooth muscle, secretion, plasma extravasation, neutrophil recruitment and cytokine activity.

Vasoactive factors produced and released by the endothelium exert a powerful influence on vascular tone in the cerebral circulation. Impaired endothelium-dependent responses, such as decreased production of endothelium-derived relaxing factors, and/or release of endothelium-derived contractile factors may give rise to different pathophysiological conditions. Among the endothelium-derived contractile factors the endothelins have recently received particular attention. Endothelin-1 is the major isoform in the endothelin family, which also includes endothelin-2 and endothelin-3. Endothelin-1 is synthesized within the endothelium of cerebral vessels, whereas both endothelin-1 and endothelin-3 in addition have been identified in neurons and glia. Recent electrophysiological work has suggested a neuromodulatory role for these peptides, but at present the general interest is mainly focused on their vasoactive role. Physiological stimuli such as hypoxia, anoxia, and hemodynamic shear stress will stimulate the endothelial endothelin production. In the brain, at least two types of specific subreceptors have been cloned; ETA receptors, exclusively associated with blood vessels and ETB receptors also found on glial, epithelial, and ependymal cells. The endothelins seem so far to be the most potent vasoconstrictors yet identified. The circulating plasma levels of immunoreactive endothelin are low. Since more than 80% of the total amount released from endothelial cells seems to be secreted towards the underlying smooth muscle, endothelins have been ascribed a local vasoregulatory role. Endothelins are believed to be involved in several of our most common cerebrovascular diseases and the present review comments on their possible pathophysiological role in subarachnoid haemorrhage, cerebral ischemia, and migraine.

That endothelin-1(ET-1) plays a mediator role in asthma is consistent with reports of ET-1-induced potentiation of cholinergic nerve-mediated contraction in airways from various animal species. This study examined the effect of ET-1 on cholinergic contractions in human isolated bronchus.Macroscopically nondiseased human bronchial tissue was obtained from 23 patients with respiratory tumours. An electrical field stimulation (EFS) frequency that produced one third of the contraction at 30 Hz (EFS30) was estimated. The effect of ET-1 on these EFS-evoked contractions was assessed.EFS-evoked contractions were frequency-dependent and abolished by either atropine or tetrodotoxin. Thus, EFS-induced contractions were mediated by acetylcholine from cholinergic nerves. ET-1 (3 nM) potentiated EFS-evoked contractions by 102% EFS30 (p<0.05) without any significant effect on contractions induced by exogenous acetylcholine.Neither the ET A receptor-selective antagonist BQ-123 (3 mM) nor the ET B receptorselective antagonist BQ-788 (10 mM) alone significantly altered ET-1-induced potentiation of EFS-evoked contractions. However, in the combined presence of both BQ-123 and BQ-788, ET-1-induced potentiation of EFS-evoked contractions was abolished.Thus, prejunctional endothelin A and endothelin B receptors appear to mediate endothelin-1-induced potentiation of electrical field stimulation-evoked cholinergic contractions in human bronchus. This suggests another potentially important mechanism through which endothelin-1 could increase bronchial tone in asthma. Eur Respir J 1999; 14: 439±442. There is growing evidence to suggest that the endogenous airway smooth muscle spasmogen endothelin (ET)-1 plays an important mediator role in asthma [1]. In addition, it has been suggested that, in some cases, asthma may be accompanied by an increase in airway cholinergic tone [2,3]. A number of agents have been shown to modulate acetylcholine release from airway nerves and there is accumulating data to indicate that ET-1 modulates cholinergic neurotransmission in the airways [4]. For example, ET peptides have been shown to markedly potentiate electrical field stimulation (EFS)-induced cholinergic contractile responses in rabbit [5,6], mouse [7,8] and rat [9] airways. These potentiations of EFS-induced contractions were mediated via activation of prejunctional ET receptors. Furthermore, data obtained in 3 H-cholineloaded rat tracheal tissue indicates that the mechanism of ET-1-induced potentiation of these responses was enhanced acetylcholine release [9]. Evidence obtained in rabbit [6], mouse [8] and rat [9] airways showed that both ET A and ET B receptors were involved in this phenomenon.A preliminary report from the authors' laboratory showed that the ET B receptor-selective agonist sarafotoxin S6c potentiated EFS-induced cholinergic contractions in human bronchus [10]. The present study significantly extends this earlier work by focusing on the role of the endogenously released ligand ET-1 which can activate ET A and ET B receptor...