Pharmacological modulation of endothelin‐induced contraction of guinea‐pig isolated airways and thromboxane release

Abstract

1The aim of the present experiments was to study the possible involvement of known bronchoconstrictor substances in mediating the myotropic action of endothelin-l (ET-1, human-porcine endothelin) in guinea-pig isolated airways. 2 ET-1 (1-100nm) caused a dose-dependent contraction of guinea-pig trachea, upper bronchus and parenchyma. The contractions developed slowly, reaching maximal values 4-6 min after addition of the peptide. 3 The contractile action of ET-1 was significantly attenuated by indomethacin (10uM), a cyclo-oxygenase blocker, BM 13505 (5,UM), a thromboxane receptor antagonist, FPL 55712 (19 pM) and YM 16638 (1pM), antagonists of the sulphidopeptide leukotrienes, BN 52021 (10pM) and WEB 2086 (1 pM), plateletactivating factor receptor antagonists in all three tissue preparations studied.4 Pretreatment of the airway tissues with compound U 75302 (3 guM), a selective leukotriene B4 receptor antagonist, or with a mixture of antagonists containing methysergide (0.75,UM), phentolamine (0.4UM), propranolol (13juM), atropine (0.4 pM) and diphenhydramine (0.45 pM) did not modify the myotropic action of ET-1. 5 ET-1, 10 and lOOnM induced three, and nine fold increases in thromboxane A2 release from lung parenchymal strips. 6 ET-1-induced thromboxane A2 release was completely abolished by indomethacin, and was significantly attenuated by BN 52021, WEB 2086 and FPL 55712. Neither BM 13505 nor YM 16638 exerted a significant effect on thromboxane release. 7 The present findings show that contraction of guinea-pig airway smooth muscle by ET-1 is mediated, in part, by the release of thromboxane A2, sulphidopeptide leukotrienes and platelet-activating factor, and suggest that the increased thromboxane A2 release following ET-1 is partly a consequence of enhanced synthesis of sulphidopeptide leukotrienes and platelet-activating factor.

Effects of endothelin‐1 on vascular permeability in the conscious rat: interactions with platelet‐activating factor

“…Recent evidence suggests that PAF may be one of these mediators. Indeed, certain effects of endothelin-1 can be attenuated by PAF receptor antagonists (Lagente et al, 1989;Takayashu et al, 1989;Terashita et al, 1989;Battistini et al, 1990;Filep et al, 1991), and endothelin-1-induced PAF synthesis has also been reported (Lopez-Farre et al, 1990 (Voelkel et al, 1986). It is also possible that the bioavailability of these antagonists is different (Kubes et al, 1990).…”

“…Indeed, PAF receptor antagonists have been reported to attenuate the bronchoconstrictor action of endothelin-1 in the guinea-pig both in vivo (Lagente et al, 1989) and in vitro (Battistini et al, 1990;Filep et al, 1991), to inhibit endothelin-1-induced increase in intracellular free calcium levels in cultured smooth muscle cells (Takayashu et al, 1989) and to protect against endothelin-1-induced sudden death in mice and rats (Terashita et al, 1989). Furthermore, endothelin-1 has recently been shown to stimulate PAF synthesis in glomerular mesangial cells (Lopez-Farre et al, 1990).…”

Induction by endothelin‐1 of epithelium‐dependent relaxation of guinea‐pig trachea in vitro: role for nitric oxide

“…A tone-dependent change in sensitivity of the trachea to NO cannot be ruled out at present. The possibility that epithelium removal led to decreased formation of bronchorelaxant prostanoids seems unlikely as under the same experimental conditions, indomethacin significantly attenuated the contractile action of ET-1 (Filep et al, 1991). Another explanation might be that under resting conditions the epithelium may function primarily as a protective (diffusion and/or metabolic) barrier, reducing the contact between agonists and airway smooth muscle.…”

“…Therefore, the relaxation experiments were performed either in the absence or in the presence of BM 13505 (5 tLM), a specific thromboxane A2/prostaglandin H2 receptor antagonist (Patscheke et al, 1987). At the concentration employed, BM 13505 neither affects prostanoid formation (Patscheke et al, 1987;Filep et al, 1991) nor interferes with the biological responses to other bronchoactive agents, including platelet-activating factor, 5-hydroxytryptamine and histamine (Patscheke et al, 1987;Battistini et al, 1990). Cumulative concentrations of ET-1 (1-100 nM) were added to intact and rubbed tracheal strips, the next concentration being added when the preceding one had reached a steady-state effect.…”

Contraction of guinea pig lung parenchyma by pancreatic type phospholipase A2 via its specific binding site

“…In conclusion, our findings reveal a new aspect of PLA2-I action in lung as a possible mediator causing broncho-constriction in pulmonary diseases such as asthma [15]. We are now conducting further studies into its pathophysiological functions, as well as its target cells in lung tissue.…”