DIFFERENT PRESSOR AND BRONCHOCONSTRICTOR PROPERTIES OF HUMAN BIG-ENDOTHELIN-1, BIG-ENDOTHELIN-2(1-38) AND BIG-ENDOTHELIN-3 IN KETAMINE XYLAZINE-ANESTHETIZED GUINEA-PIGS

1 In the present study, the precursors of endothelin-1, endothelin-2 a nd endothelin-3 were tested for their presser and bronchoconstrictor p roperties in the anaesthetized guinea-pig. In addition, the effects of big-endothelin-1 and endothelin-1 were assessed under urethane or ket amine/xylazine anaesthesia. 2 When compared to ketamine/xylazine, uret hane markedly depressed the presser and bronchoconstricter properties of endothelin-1 and big-endothelin-1. 3 Under ketamine/xylazine anaest hesia, the three endothelins induced a biphasic increase of mean arter ial blood pressure. In contrast, big-endothelin-1, as well as big-endo thelin-2 (1-38), induced only sustained increase in blood pressure whe reas big-endothelin-3 was inactive at doses up to 25 nmol kg(-1). 4 Bi g-endothelin-1, but not big-endothelin-2, induced a significant increa se in airway resistance. Yet, endothelin-1, endothelin-2 and endotheli n-3 were equipotent as bronchoconstrictor agents. 5 Big-endothelin-1, endothelin-1 and endothelin-2, but not big-endothelin-2, triggered a m arked release of prostacyclin and thromboxane A(2) 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 acti ve moieties, endothelin-1 and 2. However, the lack of bronchoconstrict or and eicosanoid-releasine properties of big-endothelin-2, as opposed to endothelin-2 or big-endothelin-1, suggests the presence of two dis tinct phosphoramidon-sensitive ECEs in the guinea-pig. The ECE respons ible for the systemic conversion of big-endothelins possesses the same affinity for big-endothelin-1 and 2 but not big-endothelin-3. In cont rast, 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.