In addition enhanced ET expressions

In addition, enhanced ET-1 expressions by those neoplastic Vinpocetine 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 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.