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

1 This study attempts to investigate if endogenous nitric oxide (NO) can mo dulate the eicosanoid-releasing properties of intravenously administered en dothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pi g. 2 The nitric oxide synthase blocker N-omega-nitro-L-arginine methyl ester ( r-NAME; 300 mu M; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A(2) (TxA(2)) stimulated by ET-1, the s elective ETB 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 guin ea-pig isolated and perfused lungs. 3 In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1-1.0 nmol kg(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol k g(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increas es in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) did not change basal PIP, but increased, in L-arginine sensitive m anner, the magnitude of the PIP increases tin both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg(-1), respec tively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg(-1)). 4 The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg(-1), respectively) or U 46619 (0.57 nmol kg(-1)) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment wit h L-NAME (5 mg kg(-1); i.v. raised basal MAP persistently and, under this c ondition, subsequent administration of ET-1 or IRL 1620, but not of U-46619 , induced hypotensive responses which were prevented by pretreatment with t he cyclo-oxygenase inhibitor indomethacin. 5 Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and presser effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ETB receptors, the release of TxA(2) in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it wo uld seem that these eicosanoid-dependent actions of ET-1 in the pulmonary s ystem and on systemic arterial resistance in this species are physiological ly dissociated.