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 modulate the eicosanoid-releasing 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(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET-1, the selective ET(B) receptor agonist IRL 1620 (Suc-[Glu9,Ala11,15]-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(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol kg(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) 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(-1), respectively), 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 with L-NAME (5 mg kg(-1); 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 effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET(B) receptors, the release of TxA2 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.
Department of Pharmacology Medical School, Université de Sherbrooke, Québec, Canada.
K
K
Lewis
A
A
Cadieux
G A
GA
Rae
J P
JP
Gratton
P
P
D'Orléans-Juste
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D015777:Eicosanoids / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D014662:Vasoconstrictor Agents; C074308:sovateltide; D009569:Nitric Oxide; C086539:BQ 788; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin