Different pressor and bronchoconstrictor properties of human big‐endothelin‐1, 2 (1–38) and 3 in ketamine/xylazine‐anaesthetized guinea‐pigs

Abstract

Texas 75235-9050, U.S.A.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-l and endothelin-l 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-'. 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-l, endothelin-l 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.

ET B Receptor Blockade Potentiates the Pressor Response to Big Endothelin-1 But Not Big Endothelin-2 in the Anesthetized Rabbit

“…This finding correlates well with the fact that the 3 natural endothelin isopeptides possess the same affinity for the ET B receptor. 17 On the other hand, we have recently shown that the pulmonary circulations of different animal species 8,9 are less efficient for conversion of big ET-2 versus big ET-1. First, in the present study, big ET-2 was much less potent than big ET-1 to induce phosphoramidon-sensitive increases in MAP.…”

“…Given that phosphoramidon equally abolished the pressor responses to either big ET-1 or big ET-2, our results suggest a more effective conversion of big ET-1 than big ET-2 by ECE, which leads to spillover of ET-1 (but not ET-2) back into the vascular compartment to evoke activation of ET B receptor-dependent release of nitric oxide. If one considers that big ET-2 (1-38) is poorly converted in the pulmonary circulation of several species, 8,9 false ECE substrates derived from the structure of the ET-2 precursor may lead to moieties that interfere with the systemic production of ETs without affecting the delicate NO/ ET-1 balance in the lungs. …”

“…8,9 Furthermore, unlike big ET-1, big ET-2 has been shown to be inactive in generating eicosanoids from perfused lungs in several animal species. 8,9 These results also suggest that tissue and cellular localizations of ECE are highly important determinants of the pressor properties of the big ETs. Though plasma big ET levels are being increasingly recognized as important markers for cardiovascular diseases, the relation between big ET processing by the ECE in vivo and the population of ET receptors subsequently activated by its active metabolite has yet to be investigated.…”

“…2,6,7 On the other hand, we have shown in the guinea pig in vivo that big ET-1 and big ET-2 have different vasopressor and bronchoconstrictor profiles of action, which possibly reflects the differential affinity of the latter peptide for ECE of the systemic vasculature compared to that of the pulmonary circulation. 8,9 Furthermore, unlike big ET-1, big ET-2 has been shown to be inactive in generating eicosanoids from perfused lungs in several animal species. 8,9 These results also suggest that tissue and cellular localizations of ECE are highly important determinants of the pressor properties of the big ETs.…”

“…8,9 Furthermore, unlike big ET-1, big ET-2 has been shown to be inactive in generating eicosanoids from perfused lungs in several animal species. 8,9 These results also suggest that tissue and cellular localizations of ECE are highly important determinants of the pressor properties of the big ETs.…”