Comparison of the cardiovascular and neural activity of endothelin‐1, −2, −3 and respective proendothelins: effects of phosphoramidon and thiorphan

Mattera, Giovan Giuseppe; Eglezos, Anthony; Renzetti, Anna Rita; Mizrahi, Jacques

doi:10.1111/j.1476-5381.1993.tb13813.x

Cited by 15 publications

(4 citation statements)

References 40 publications

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“…All these responses were blocked by phosphoramidon, but the ECE/NEP inhibitor had no effect on the actions of the mature peptide. Similar results were obtained in the anesthetized, ganglion-blocked rat, where intravenous bolus doses of Big ET-2 were compared with Big ET-1 where the cardiovascular actions of both peptides were prevented, as expected, by phosphoramidon but not thiorphan ( Mattera et al, 1993 ).…”

Section: Endothelins and Sarafotoxinssupporting

confidence: 75%

Endothelin

et al. 2016

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The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

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Section: Endothelins and Sarafotoxinssupporting

confidence: 75%

Endothelin

et al. 2016

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“…Similar results were obtained in the anaesthetized, ganglion‐blocked rat, where intravenous bolus doses of Big ET‐2 were compared with Big ET‐1. The onset of the vasopressor effect was more rapid (5–6 min) for the latter than that of Big ET‐2 (10–13 min) but the actions of both peptides were blocked as expected by phosphoramidon but not thiorphan (Mattera et al ., 1993). In renal adenocarcinoma cells producing high levels of ET‐2, the presence of ECE was confirmed by sequencing (Yorimitsu et al ., 1992; 1995).…”

Section: Does Et‐2 Have a Separate Synthesis From Other Et Peptides?mentioning

confidence: 67%

Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

Ling

Maguire

Davenport

2012

British J Pharmacology

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Endothelin-2 [ET-2; also known as vasoactive intestinal contractor (VIC), in rodents] differs from endothelin-1 (ET-1) by only two amino acids, and unlike the third isoform, endothelin-3 (ET-3), it has the same affinity as ET-1 for both ETA and ETB receptors. It is often assumed that ET-2 would mimic the actions of the more abundant ET-1 and current pharmacological interventions used to inhibit the ET system would also block the actions of ET-2. These assumptions have focused research on ET-1 with ET-2 studied in much less detail. Recent research suggests that our understanding of the ET family requires re-evaluation. Although ET-2 is very similar in structure as well as pharmacology to ET-1, and may co-exist in the same tissue compartments, there is converging evidence for an important and distinct ET-2 pathway. Specifically is has been demonstrated that ET-2 has a key role in ovarian physiology, with ET-2-mediated contraction proposed as a final signal facilitating ovulation. Furthermore, ET-2 may also have a pathophysiological role in heart failure, immunology and cancer. Comparison of ET-2 versus ET-1 mRNA expression suggests this may be accomplished at the level of gene expression but differences may also exist in peptide synthesis by enzymes such as endothelin converting enzymes (ECEs) and chymase, which may allow the two pathways to be distinguished pharmacologically and become separate drug targets. LINKED ARTICLESThis article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi. org/ 10.1111/bph.2013.168.issue-2 Abbreviations ECE-1, endothelin converting enzyme 1; ECE-2, endothelin converting enzyme 2; ELISA, enzyme-linked immunosorbent assay; HIFs, hypoxia-inducible factors; MEK1/2, mitogen-activated protein kinase kinase; MMP-2, matrix metallopeptidase 2; MMP-9, matrix metallopeptidase 9; NEP, neutral endopeptidase; PRKO, progesterone receptor knockout; PMA, phorbol 12-myristate 13 acetate; VIC, vasoactive intestinal contractor IntroductionThe existence of a peptidic endothelium-derived constricting factor was originally proposed in 1985 by Hickey et al. (Hickey et al., 1985) but was identified and named endothelin (ET) by colleagues in 1988 (Yanagisawa et al., 1988). The peptide was renamed ET-1 to reflect the subsequent discovery a year later of human genes encoding two further members of the family, ET-2 and ET-3 (Inoue et al., 1989). The ET peptides act by activating two G-protein couples receptors, ETA and ETB. (Davenport, 2002;Alexander et al., 2011) ET-3 is the only endogenous isoform that distinguishes between the two receptors, having the same affinity at ETB as ET-1 and ET-2 but, at physiological concentrations, has much lower or little affinity for ETA. The established dogma is that ET-2 has the same affinity for both ETA and ETB receptors as ET-1. It is often assumed that ET-2 would mimic the actions of the more abundant peptide, and current pharmacological interventions used to inhibit the ET system would also block the actions o...

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“…a phosphoramidon-sensitive pressor effect, demonstrating an interspecies variation in the ECE activity (Gardiner et al, 1992;Matsumura et al, 1993;Mattera et al, 1993;Pollock et al 1993). Furthermore, Matsumura et al (1993) have suggested that different conditions of anaesthesia as well as the use of a ganglion blocker enhanced the pressor activity of big-endothelin-3 in the rat model.…”

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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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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Comparison of the cardiovascular and neural activity of endothelin‐1, −2, −3 and respective proendothelins: effects of phosphoramidon and thiorphan

Cited by 15 publications

References 40 publications

Endothelin

Endothelin

Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

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

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