Inhibition of biological actions of big endothelin-1 by phosphoramidon

Fukuroda, Takahiro; Noguchi, Kazuhito; Tsuchida, Sonoko; Nishikibe, Masaru; Ikemoto, Fumihiko; Okada, Kenji; Yano, Mitsuo

doi:10.1016/0006-291x(90)90685-g

Cited by 141 publications

(61 citation statements)

References 9 publications

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“…Like big-endothelin-l, big-endothelin-2 is also a potent pressor agent in the guinea-pig. Furthermore, we have shown that the pressor responses to big-endothelin-2 are phosphoramidonsensitive, suggesting that the conversion pathway for bigendothelin-2 in the systemic circulation is similar to that reported for big-endothelin-1 (Fukuroda et al, 1990;D'Orleans-Juste et al, 1991b).…”

Section: Resultssupporting

confidence: 82%

“…Similarly to endothelin-1, big-endothelin-1 is also a potent pressor and bronchoconstrictor agent (Kashiwabara et al, 1989;Fukuroda et al, 1990;D'Orleans-Juste et al, 1991b). Yet, unlike endothelin-1, both effects of big-endothelin-1 are suppressed by phosphoramidon, suggesting that the latter peptide must be converted to its active metabolite via an endothelin-converting enzyme (ECE) which is sensitive to this neutral endopeptidase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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

Gratton

Rae

Claing

et al. 1995

British J Pharmacology

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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.

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Section: Resultssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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

Gratton

Rae

Claing

et al. 1995

British J Pharmacology

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“…This finding is in agreement with the results of Kashiwabara et al (1989) but not with those of MacMahon et al (1989) who obtained a pressor effect with a 40 amino acid pproendothelin only when the peptide was injected after preincubation with chymotrypsin. Recent publications (Fukuroda et al, 1990;Matsumura et al, 1990c;McMahon et al, 1991) and this investigation demonstrate that the pressor effects of h-proendothelin in pithed rats can be inhibited dosedependently by phosphoramidon which is a metallopeptidase inhibitor. This finding allows the conclusion that the functional effects of h-proendothelin are mediated by endothelin-1 unless phosphoramidon is a blocker of a specific receptor for h-proendothelin.…”

Section: Discussionmentioning

confidence: 60%

Cross tachyphylaxis to endothelin isopeptide‐induced hypotension: a phenomenon not seen with proendothelin

Gouville

Cavero

1991

British J Pharmacology

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1 In anaesthetized rats, an i.v. injection of endothelin-1 (0.25nmolkg-') evoked a rapidly appearing (maximal effect within 15 s) and short lasting (3 min) fall in blood pressure with tachyphylaxis occurring so that it was reduced by 50% by the last of 4 injections given 10 min apart. This property was also shared by endothelin-2, endothelin-3 and vasoactive intestinal contractor (VIC). 2 Cross tachyphylaxis between the isopeptides occurred. However, under the same experimental conditions the hypotensive effects of acetylcholine, adenosine, atrial natriuretic peptide (ANP) and substance P were reproducible and not modified in animals in which endothelin-1 no longer lowered blood pressure. Thus, the mechanism of the hypotensive action of endothelin peptides is different from that of acetylcholine, adenosine, ANP, and substance P. 3 In pithed rats, endothelin-1 (0.25 nmol kg-')and its precursor human proendothelin (h-proendothelin) (0.5nmolkg-') induced pressor responses of a similar magnitude, which for h-proendothelin (up to 5.0 nmol kg'-) were not preceded by a hypotensive phase. The pressor effects of endothelin-1, like those of vasopressin, were reproducible upon repeated i.v. injections. 4 Rats given a 10min infusion (0.1 nmol kg-min-1) of endothelin-1 showed no hypotensive response to an i.v. bolus injection of endothelin-1, whereas animals pretreated with an equipressor infusion of hproendothelin did not develop tachyphylaxis to endothelin-1. 5 In pithed rats, endothelin-1, at a dose inducing the same maximal increase in blood pressure as hproendothelin, was approximately 3 fold more potent as a mesenteric vasoconstrictor than hproendothelin. These results suggest that if h-proendothelin is processed to endothelin-1, this transformation is not uniform throughout the vascular system. 6 The pressor response of h-proendothelin in pithed rats was dose-dependently inhibited by phosphoramidon (2.5-5.0mgkg '). However, this compound did not antagonize the effects of endothelin-1 (0.25 nmol kg-) or those of h-proendothelin (0.5 nmol kg-) once developed. 7 Although some of these results may suggest that h-proendothelin does not undergo in vivo conversion to endothelin-1, the results obtained with phosphoramidon suggest that h-proendothelin is converted into endothelin-1. Therefore, the amount of endothelin-1 so produced can elicit pressor responses or regional vasoconstriction, but is insufficient to lower blood pressure and to inhibit endothelin-1-induced hypotension. 8 The mechanism of the tachyphylaxis does not appear to be depletion of endothelium-derived relaxing factor, since agents coupled to the latter endogenous vasorelaxant substance do not exhibit crosstachyphylaxis with endothelin-1. It is suggested that upon repeated or sustained exposure to endothelin-1, the endothelin-1 receptors mediating hypotension decrease in number and/or undergo conformational changes making them refractory to activation. Alternatively, the depletion of a blood-borne agent responsible for the hypotension could be involved.

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“…Endothelial cells possess a membrane-bound neutral metalloprotease exhibiting ECE activity (28), which is inhibited by a relatively high concentration of phosphoramidon (29). Both in vivo and in vitro, exogenously applied big endothelin-1 is rapidly converted, suggesting that the conversion takes place at the cell surface (30). The conversion from big endothelin-1 to endothelin-1 is essential for exertion of biological activity, because the pressor action of big endothelin-1 was almost completely inhibited by a relatively large dose of phosphoramidon (31,32).…”

Section: -1 Endothelin Gene and Regulation Of Its Expressionmentioning

confidence: 99%

“…After more than six years, the cloning and characterization of ECE have finally been successfully achieved. ECE is considered to be a potential target for selectively interrupting the biosynthesis of endothelin; although this approach has proven to be extremely difficult, an N-and C-terminaltruncated analogue of big endothelin-1 , [Phe22] big endothelin-1 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], was recently shown to be a potent inhibitor of ECE-1, being at least 30-fold more potent that phosphoramidon in blocking big endothelin-linduced vasoconstriction in the kidney (38).…”

Section: -1 Endothelin Gene and Regulation Of Its Expressionmentioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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Inhibition of biological actions of big endothelin-1 by phosphoramidon

Cited by 141 publications

References 9 publications

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

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

Cross tachyphylaxis to endothelin isopeptide‐induced hypotension: a phenomenon not seen with proendothelin

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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