Potential Clinical Implications of the Urotensin II Receptor Antagonists

Abstract

Urotensin II (UII) binds to its receptor, UT, playing an important role in the heart, kidneys, pancreas, adrenal gland, and central nervous system. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, however, this constriction–dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome, and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) activity leading to smooth muscle cell proliferation and foam cell infiltration, insulin resistance (DMII), as well as inflammation, high blood pressure, and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

Pressor and renal regional hemodynamic effects of urotensin II in neonatal pigs

“…Data are expressed as meanGS.E.M. AngII and losartan were co-administered to the piglets w10 min after intrarenal arterial bolus injection of losartan Ross et al 2010, Tsoukas et al 2011. However, the cyclic hexapeptide sequence in UII carboxyl-terminus, which is responsible for its biological activity, is highly conserved between species (Itoh et al 1987, Conlon et al 1990, Coulouarn et al 1998, Douglas et al 2004.…”

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…As a matter of fact, treatment of streptozotocin-induced diabetic rats with palosuran (Clozel et al, 2004) improves survival, increases serum insulin concentration, reduces glycemia, attenuates albuminuria, and prevents renal tubular degeneration (Clozel et al, 2006). However, clinical trials led to divergent results (Desai et al, 2008;Tsoukas et al, 2011). One study indicates that, in hypertensive T2DM patients affected by nephropathy, palosuran (125 mg twice daily) reduces albuminuria, suggesting that blockage of UT could be a therapeutic approach for the treatment of diabetic nephropathy (Sidharta et al, 2006).…”

“…Clinical studies have provided evidence that UII and UT are implicated in various pathologies, including cardiovascular diseases Ng et al, 2002;Richards et al, 2002;You et al, 2012;Watson et al, 2013), renal diseases , and diabetes (Wenyi et al, 2003;Sidharta et al, 2009). The various activities of UII and the potential implication of the urotensinergic system in various pathologies have prompted academic laboratories and pharmaceutical companies to design specific agonists and antagonists that are currently used for basic research and may lead to therapeutic applications Maryanoff and Kinney, 2010;Tsoukas et al, 2011;Merlino et al, 2013).…”

Small molecule and peptide therapies for chronic heart failure: a patent review (2011 – 2014)

“…Urotensin-II is a potent cyclic peptide vasoconstrictor [127]. Plasma urotensin-II and receptor levels are elevated in heart failure [128]. Urotensin-II receptor antagonists have been developed in order to treat a number of cardiovascular conditions, including heart failure [129].…”