Nitric oxide limits the eicosanoid-dependent bronchoconstriction and hypotension induced by endothelin-1 in the guinea-pig (original) (raw)

Abstract

This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoidreleasing properties of intravenously administered endothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pig. 2 The nitric oxide synthase blocker N o-nitro-L-arginine methyl ester (L-NAME; 300 mM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A 2 (TxA 2) stimulated by ET-1, the selective ET B receptor agonist IRL 1620 (Suc-[Glu 9 ,Ala 11,15 ]-ET-1(8-21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea-pig isolated and perfused lungs. 3 In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1 ± 1.0 nmol kg 71), IRL 1620 (0.2 ± 1.6 nmol kg 71), BK (1.0 ± 10.0 nmol kg 71) or U 46619 (0.2 ± 5.7 nmol kg 71) each induced dose-dependent increases in pulmonary insuation pressure (PIP). Pretreatment with L-NAME (5 mg kg 71) did not change basal PIP, but increased, in L-arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg 71 , respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg 71). 4 The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg 71 , respectively) or U 46619 (0.57 nmol kg 71) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L-NAME (5 mg kg 71 ; i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET-1 or IRL 1620, but not of U-46619, induced hypotensive responses which were prevented by pretreatment with the cyclo-oxygenase inhibitor indomethacin. 5 Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and pressor eects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET B receptors, the release of TxA 2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid-dependent actions of ET-1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

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