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  • This relative lack of ET expression in


    This relative lack of ET-1 expression in highly malignant epithelial Atropine could be explained by marked cellular anaplasia and cellular dysfunction; we also suggest that the high levels of VEGF, which have been evidenced in highly malignant mammary tumours (Restucci et al., 2002) may suppress ET-1 synthesis via a negative feed-back mechanism. In addition, enhanced ET-1 expressions by those neoplastic cells which are located near to necrotic areas, in G2 and mostly in G3 carcinomas, strongly suggest a positive feedback between tissue hypoxia and ET-1. Thus, this confirms that hypoxia is a potent angiogenetic stimulator and that it can indirectly enhance neoplastic growth and invasiveness through ET-1 release. This highlights the link between hypoxia and the increased invasiveness in malignant tumours through the synthesis of angiogenic cytokines (Shweiki et al., 1992). It has been demonstrated in human breast cancer that invasiveness may be reduced by selective ETAR antagonism, thereby confirming the ET-1 involvement; this emphasizes the potential therapeutic usefulness of ETAR antagonists (Smollich et al., 2008). Therefore, elucidating further the cellular mechanisms triggered by ET-1/ETAR interaction may open an new avenue to develop chemotherapy protocols for canine mammary tumours; yet, not only, we also believe that ET-1/ETAR expression in spontaneous canine mammary tumour may add additional interest in this animal model for improving human breast cancer therapy.
    All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, although ET-1 is the predominant isoform. ET-1 and ET-2 bind to two G-protein–coupled receptors, ET and ET, whereas at physiological concentrations ET-3 has little affinity for the ET receptor. The endothelin receptors are members of the Family A G-protein–coupled receptors, a class of proteins that has been exploited very successfully as targets for the development of drugs. The human kidney is unusual among the peripheral organs in expressing a high density of ET. The renal vascular endothelium only expresses the ET subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ET in kidney, as well as liver and lungs, has a critical role in scavenging ET-1 from the plasma. The third major function is for Atropine ET-1 activation of ET in medullary epithelial cells to reduce salt and water reabsorption. ET predominate on the vasculature to cause vasoconstriction. The pathophysiological actions of ET-1 are mediated mainly via the ET subtype. The role of the two subtypes has been delineated in preclinical and acute experimental studies using highly selective ET (including BQ123, TAK-044) and ET (BQ788) peptide antagonists. Three nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET/ET antagonists or display ET selectivity, have been approved for clinical use, primarily in pulmonary arterial hypertension. In renal pathophysiological conditions ET-1 contributes to vascular remodeling, proliferation of mesangial cells, and extracellular matrix production, mainly through binding to ET. Beneficial actions of ET-1 on sodium and water regulation mainly are ET-mediated. These findings suggest an ET-selective antagonist would have a therapeutic advantage over a mixed antagonist in renal disease. Acute studies directly comparing mixed and selective peptide antagonists suggest selective ET blockade, however, sparing ET may be beneficial. However, this was balanced by a greater prevalence of side effects for small-molecule, orally active ET antagonists compared with mixed antagonists, although the latter also have their limitations. The ET signaling pathway in the kidney remains a promising clinical target for receptor antagonism, which may be realized by the next generation of antagonists. ET Receptors The ET family comprises three isoforms, ET-1, ET-2, and ET-3.1, 2 Although messenger RNA encoding all three has been detected in human kidney, ET-1 is the predominant intrarenal isoform. ETs interact with two distinct G-protein–coupled receptors, ETA and ETB (Fig. 1), which were identified 2 years after the discovery of the endogenous peptides in 1988. They are both class A, G-protein–coupled receptors; this class is the target of nearly half of currently available medicines. This has resulted from well-developed medicinal chemistry strategies and high-throughput screening programs to identify small-molecule drugs, stimulating considerable effort to discover ET-receptor antagonists. The initial clue to the existence of two subtypes and the key to classifying the receptors was that ET-1 and ET-2 are equipotent at the ETA subtype whereas ET-3 shows at least 100-fold lower potency and at physiological concentration ET-3 is unlikely to activate this subtype (Table 1). All three ETs bind to ETB with similar affinity.6, 7 This review focuses on the role of ET receptors in the human kidney and considers the clinical pharmacology of ET antagonists that have been used to block these receptors. The effects of ET-1 on the kidney are complex and more detailed information can be found in reviews on renal endothelin physiology and pathology, and the pharmacology of the endothelin signaling pathway.10, 11