Palosuran as perspective new antihypertensive remedy

Abstract

Nowadays, pharmacotherapy and treatment of hypertension disease still remains an actual problem by reason of the side effects of existing antihypertensive medicines. Lowering blood pressure in itself remains the preeminent mechanism by which antihypertensive drugs provide cardiac, cerebral, renal, and vascular benefits for patients. In recent last years, have been increased interest of the cyclic vasoactive neuropeptide urotensin-2 (U-II), which is characterized by strong vasoconstrictor features. Increased secretion of U-II and excessive expression of UT-II receptors (UTR) have been identified in some several pathologies, including hypertension. So the role of the U-II/ UTR systems in the extension and development of hypertension are less studied. Information about effects of U-II receptor antagonist – Palosuran on blood arterial pressure is scanty, limited and contradictory. Therefore also, accordingly we aimed to study the effect of Palosuran on systemic blood pressure (SBP) in the lab. rats using H.Goldblatt method of experimental hypertension (2 kidneys + 1 clip). In experimental animals with hypertension, Palosuran was administered intraperitoneally (10 mg/kg once daily, during 4 weeks) and at the end of treatment, NO-synthase inhibitor LNAME (10 mg/kg) was injected intraperitoneally as well. Blood pressure was measured non-invasively, using the systolic blood pressure measurement system “Систола” (“tail cuff“ method). The study results have shown that after 4 weeks of blood hypertension modeling a stable and progressive increase in blood pressure was detected due to the complex action of rennin-angiotensin-aldosteron (RAAS) and sympathetic nervous systems activity. The latter enhances renin production and peripheral vasoconstriction. After treatment with Palosuran, a statistically significant decrease in SBP was observed in all study group animals supposedly through an antagonistic effect on UTR. According to the literature UG-2 in small doses active production of NO (by activating NO-synthase) leading to the dilation of blood vessels as an endothelin-dependent vasodilator. After administration of LNAME, there was an unreliable increase in systemic blood pressure (SBP) compared to animals treated with Palosuran. Compared to control (untreated) group rats, systemic blood pressure was significantly reduced only in case when treatment was started earlier (at early stage of hypertension). Administration of LNAME, as a NO-synthase inhibitor, should have increase systemic blood pressure that was not detected in palosuran-treated group rats, especially at the early stage of hypertension. Supposedly, Palosuran, inhibiting the effect of urotensin, increases NO production and thereby reduces the vasoconstrictive effect of LNAME. The antihypertensive effect of Palosuran was less expressed at late stages of hypertension. Supposedly, due to the blood vessels injury as a result of longstanding hypertension, increasing UG-2 production thereby supporting manifestation of endothelin-independent vasoconstrictive effect of urotensin. Palosuran reveals hypotensive effect in both, healthy and hypertensive rats, and even after administration of LNAME supposedly, due to its UTR antagonistic and vasodilatory effect. In lab. rats the vasodilating effect of palosuran outweighs the inhibitory effect of LNAME on NO and UR-induced endothelial-independent vasoconstrictive effect, especially in the early stages of hypertension.