Effect of endothelin-1 on pulmonary resistance in rats

1 Endothelin-1 potently contracts smooth muscle, including that in the airways. However, its effect on airway mucosal function has not so far been studied. 2 We have used the ferret whole trachea in vitro to examine the effect of endothelin-1 on tracheal smooth muscle tone, transepithelial potential difference (p.d.), submucosal gland secretion (including lysozyme secretion from serous cells) and active epithelial albumin transport. In addition we have examined the effects of endothelin on submucosal gland secretion and albumin transport pre-stimulated with the muscarinic agonist methacholine and the a-adrenoceptor agonist phenylephrine. The effects of the Ca2+ channel blocker nifedipine on the responses to endothelin have also been assessed. 3 Endothelin (O.1-100 nM) produced concentration-dependent increases in intraluminal tracheal pressure indicating smooth muscle contraction, and in the negativity of the transepithelial p.d. These effects were partially inhibited by nifedipine (1OpM).4 Endothelin (0.01-100nM) had no significant effect on baseline rates of mucus, lysozyme or albumin outputs, but produced concentration-dependent reductions in maintained methacholine-and phenylephrine-induced mucus, lysozyme and albumin outputs. In general endothelin was more potent against methacholine-induced effects. All of the concentration-response curves for endothelin were shallow and some appeared to be biphasic, suggesting the possibility of more than one mechanism of action of endothelin. 5 The effects of endothelin (at concentrations > nM) on phenylephrine-induced mucus volume, lysozyme and albumin outputs were significantly inhibited by nifedipine. Similarly the effect of endothelin (>1 nM) on methacholine-induced mucus volume and albumin outputs (but not lysozyme output) was attenuated by nifedipine. The effects of endothelin (at concentrations <1 nM) on methacholine and phenylephrine-induced responses were generally not affected by nifedipine. 6 Thus, endothelin contracts ferret tracheal smooth muscle and increases transepithelial p.d. at least in part by opening dihydropyridine-sensitive Ca2+ channels. Endothelin does not directly stimulate submucosal gland secretion or epithelial albumin transport, but inhibits methacholine-and phenylephrineinduced secretion and transport. The inhibitory effects produced by higher concentrations of endothelin may be mediated partially by activation of dihydropyridine-sensitive Ca2+ channels, although the explanation for this is not clear. The mechanism of action of endothelin in attenuating stimulated secretion and epithelial transport at lower concentrations is unknown.

Section: Effects Of Nifedipinesupporting

confidence: 93%

“…Endothelin produced a concentration-dependent increase in intraluminal tracheal pressure, indicating contraction of the tracheal smooth muscle. These results are consistent with previous studies showing endothelin to be a potent bronchoconstrictor in vivo (Matsuse et al, 1990) and in vitro on isolated preparations from a number of species, including man In test tracheae, responses to methacholine and phenylephrine immediately before and during exposure to nifedipine are shown. There are no significant differences (P > 0.05, paired t test) in initial and maintained responses between control and test tracheae.…”

Section: Effects Of Endothelin On Responses To Methacholine and Phenysupporting

confidence: 92%

Endothelin‐1 inhibits pre‐stimulated tracheal submucosal gland secretion and epithelial albumin transport

Yurdakos

Webber

1991

“…They affected only slightly the mean arterial blood pressure after the onset of seizures, but greatly reduced the end-inspiratory airway pressure, indicating that the increase in airway resistance was directly or indirectly due to liberation of endogenous ET. ET-1 is a potent bronchoconstrictor, which even upon intravenous application triggers a long lasting increase in airway resistance in rats (Matsuse et al, 1990). The increases in airway pressure in our experiments could functionally be related to bronchoconstriction and/or oedema formation, which cannot be differentiated from our results.…”

Section: Discussioncontrasting

confidence: 59%

“…and ET doses used (Filep, 1993). ET may elicit pulmonary vasoconstriction (Horgan et al, 1991;Raffestin et al, 1991), induce bronchoconstriction (Matsuse et al, 1990) and release 15S-hydroxyeicosatetraenoic acid ), another vasoconstrictor able to trigger pulmonary oedema (Burhop et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

A role for endothelin in bicuculline‐induced neurogenic pulmonary oedema in rats

Herbst

Tippler

Shams

et al. 1995

1 The possible contribution of endogenous endothelin (ET) to the pathogenesis of seizure-associated pulmonary oedema was examined in mechanically ventilated rats after intravenous bolus injection of the y-aminobutyric acid (GABA) antagonist, bicuculline (1.2 mg kg-'). 2 Recurrent seizure activity elicited by bicuculline injection led to rapidly developing pulmonary oedema. Within 4 min after bicuculline application (1.2 mg kg-'), arterial 02 partial pressure (PaO2) significantly dropped from 17.49 ± 1.20 kPa to 7.51 ± 2.21 kPa (P< 0.01) and arterial CO2 partial pressure (Paco2) significantly increased from 4.64 ± 0.56 kPa to 8.15 ± 0.99 kPa (P <0.01). Gradually a progressive acidosis developed. Moreover, mean arterial blood pressure (MABP) and end-inspiratory airway pressure (Paw) rapidly increased. 3 Concomitantly there was a time-dependent increase of big ET-1 and ET-1 levels in bronchoalveolar lavage (BAL) as determined by combined reverse phase high performance liquid chromatography (h.p.l.c.) and radioimmunoassay. BAL levels of both peptides increased up to 8 min after bicuculline injection and slowly decreased subsequently. In contrast, BAL from animals injected with vehicle did not contain detectable amounts of ET. 4 Pretreatment with the endothelin-converting enzyme inhibitor, phosphoramidon (5.4 mg kg', i.v.) for 5 min significantly (P <0.001) reduced peak ET-1 levels in BAL fluid by 65.4 ± 9.9% at 8 min after bicuculline injection. Simultaneously it afforded protection from hypoxia. PaCo2 did not increase and Pa02 decreased only slightly from 14.63 ± 1.00 kPa to 12.97 ± 0.61 kPa (P> 0.05) after phosphoramidon pretreatment. In contrast, vehicle-treated animals that received bicuculline showed both significant hypercapnia as well as profound hypoxia. Phosphoramidon significantly diminished the maximum increase in Paw by 76.7 ± 12.4% (P <0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis.

“…Specific binding sites for ET have been detected in airways, particularly the smooth muscle, of various species including man Turner et al, 1989;Kanse et al, 1989;Hemsen et al, 1990;Henry et al, 1990). Furthermore, ET-1 is a potent contractile agonist of mammalian airways both in vitro and in vivo (Payne & Whittle, 1988;Uchida et al, 1988;Lagente et al, 1989;Macquin-Mavier et al, 1989;Turner et al, 1989;Maggi et al, 1989;1990;Hay, 1990;Hemsen et al, 1990;Matsuse et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Relative contributions of direct and indirect mechanisms mediating endothelin‐induced contraction of guinea‐pig trachea

Hay

Hubbard

Undem

1993

1 The present study was undertaken to determine the mechanism of action of endothelin-l (ET-l)-induced contraction of the guinea-pig isolated trachea.2 ET-1 (1 nM-0.3 piM) produces a concentration-dependent contraction of guinea-pig trachea with an EC50 of approximately 25 nM. The combination of the peptidoleukotriene receptor antagonist, SK&F 104353 (10 JM) and the HI-histamine receptor antagonist, mepyramine (10 pM), which abolishes antigeninduced contraction in guinea-pig trachea, was without effect on ET-1 concentration-response curves.Furthermore, the platelet-activating factor (PAF) receptor antagonist, WEB 2086, (1 or 1O pM) did not inhibit ET-induced contraction. 3 ET-l (0.3 jiM) did not stimulate histamine or immunoreactive peptidoleukotriene release from guinea-pig isolated trachea. 4 The release of various prostanoids from guinea-pig trachea was increased significantly by ET-1 (0.3 jiM); the profile of release was prostaglandin D2 (PGD2) = PGE2 = 6-keto PGFi,, (PGI2 metabolite)> thromboxane B2 = PGFk >> 9a, 111, PGF2 (PGD2 metabolite). ET-1-induced release of prostaglandins, which was about 30% of that elicited by antigen in sensitized tissues, was not affected by epithelium removal and was observed in tissues from which the smooth muscle had been removed. Previous studies in our laboratory indicated that indomethacin potentiated contraction produced by high concentrations of ET-1, whereas a thromboxane receptor antagonist was without appreciable effect on ET-l concentration-response curves.5 Pretreatment of tissues for 1 h with capsaicin (1O jiM), which depletes different sensory neurones, produced a small, but significant, inhibitory effect on ET-1 concentration-response curves in the presence but not the absence of the epithelium. The combination of the NK, tachykinin receptor antagonist, CP-96,345 (0.1 pM), and the NK2 tachykinin receptor antagonist, SR 48968 (0.1 jiM), was without effect on ET-l concentration-response curves but substantially antagonized capsaicin-induced contraction. 6 The present data suggest that in guinea-pig isolated trachea, ET-1 produces contraction predominantly via a direct mechanism: there is no significant contribution of the release of histamine, leukotrienes, PAF, or tachykinins (acting on NK, or NK2 receptors). Although ET-1 evokes the release of an array of prostanoids from the trachea they do not appear to have a major influence on the contractile response.