Different pressor and bronchoconstrictor properties of human big-endothelin-1, 2 (1-38) and 3 in ketamine/xylazine-anaesthetized guinea-pigs.
1. In the present study, the precursors of endothelin-1, endothelin-2 and endothelin-3 were tested for their pressor and bronchoconstrictor properties in the anaesthetized guinea-pig. In addition, the effects of big-endothelin-1 and endothelin-1 were assessed under urethane or ketamine/xylazine anaesthesia. 2. When compared to ketamine/xylazine, urethane markedly depressed the pressor and bronchoconstrictor properties of endothelin-1 and big-endothelin-1. 3. Under ketamine/xylazine anaesthesia, the three endothelins induced a biphasic increase of mean arterial blood pressure. In contrast, big-endothelin-1, as well as big-endothelin-2 (1-38), induced only sustained increase in blood pressure whereas big-endothelin-3 was inactive at doses up to 25 nmol kg-1. 4. Big-endothelin-1, but not big-endothelin-2, induced a significant increase in airway resistance. Yet, endothelin-1, endothelin-2 and endothelin-3 were equipotent as bronchoconstrictor agents. 5. Big-endothelin-1, endothelin-1 and endothelin-2, but not big-endothelin-2, triggered a marked release of prostacyclin and thromboxane A2 from the guinea-pig perfused lung. 6. Our results suggest the presence of a phosphoramidon-sensitive endothelin-converting enzyme (ECE) which is responsible for the conversion of big-endothelin-1 and big-endothelin-2 to their active moieties, endothelin-1 and 2. However, the lack of bronchoconstrictor and eicosanoid-releasing properties of big-endothelin-2, as opposed to endothelin-2 or big-endothelin-1, suggests the presence of two distinct phosphoramidon-sensitive ECEs in the guinea-pig. The ECE responsible for the systemic conversion of big-endothelins possesses the same affinity for big-endothelin-l and 2 but not big-endothelin-3. In contrast, in the pulmonary vasculature is localized in the vicinity of the sites responsible for eicosanoid release, an ECE which converts more readily big-endothelin-1 than big-endothelin-2.
Gratton
J P
JP
Department of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
Rae
G A
GA
Claing
A
A
Télémaque
S
S
D'Orléans-Juste
P
P
D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007649:Ketamine; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism; D014520:Urethane; D014991:Xylazine
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D014991:Xylazine; D014520:Urethane; D013928:Thromboxane A2; D007649:Ketamine; D011464:Epoprostenol; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon