Urantide is a UⅡ receptor antagonist. It can effectively alleviate monocrotaline (MCT)-induced PAH in a rat model, probably by relaxing pulmonary arteries and blocking pulmonary vascular remodeling. And it is also endowed with high affinity for human UⅡ receptors. Urantide provides an intriguing tool in the field of alternative pharmacological strategies, because negative modulation of the urotensinergic system can be useful in the treatment of various diseases such as atherosclerosis and colon cancer.
Urantide selectively blocks hU-Ⅱ-induced effects in the rat aorta, being unable to modify the responses produced by different spasmogenic compounds. Urantide produced a concentration related competitive inhibition of hU-Ⅱ-induced contractions. It failed to modify noradrenaline induced contractile responses or ET-1-induced contractile responses. Urantide failed to modify acetylcholine-induced relaxations in noradrenaline precontracted preparations bearing intact endothelium. Urantide competitively antagonizes the pro-contraction effect of UII in the chest aorta of rats and markedly inhibits the increase of UII activity in human monocyte-derived macrophages, thereby blocking the development and accumulation of foam cells.
Urantide inhibited the proliferation of vascular smooth muscle cells and the expression of U-II and GPR14. It treatment improved right heart failure parameters in MCT-induced pulmonary arterial hypertension (PAH) rats, thus providing a potential new strategy for treating PAH.
Pharmacokinetics and metabolism
Urantide was administrated by different duration of treatment to observe whether urantide protects against AS and blocks the development of AS. As a result, Urantide resulted in reductions in the concentrations of TG, TC, HDL and LDL in blood serum and reductions in the immunohistochemical intensity and range in the plaques of the aortic tunica intima and tunica media compared with the model group. Urantide also resulted in reductions in the gene and protein expression levels of UII and GPR14. Furthermore, as the injections of urantide continued, the therapeutic effect became more evident. Urantide binds with nanomolar affinity to the recombinant hUT and antagonizes the contractile effects of urotensin-Ⅱ in the rat aorta without showing any residual agonist activity.
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