Urotensin-2 Receptor Antagonist - Palosuran Decreases Blood Pressure And Plasma Renin Concentration In Laboratory Rats With Renovascular Hypertension

Kajaia Albina, Gabunia Luiza, Ketevan Ghambashidze, Nino Gogokhia, Londa Rukhadze

Abstract


We were aimed to study effects of the Urotensin-2 receptor antagonist - Palosuran on blood pressure and plasma rennin concentration in laboratory rats with renovascular hypertension (2 kidneys + 1 clip).  Blood pressure was measured using noninvasive “tail cuff“ method.

Studies have shown that in experimental rats palosuran (10 mg/kg/daily, during 4 weeks) reveal hypotensive effect. Blood pressure was decreased even after administration NO-synthase inhibitor - L-NAME (10 mg/kg, single dose), supposedly due to its urotensin-2 receptor antagonistic properties.

In hypertensive rats plasma renin concentration was increased progressively compared to the data of healthy rats. In palosuran-treated hypertensive rats  renin concentration was significantly lower than in untreated hypertensive rats. Decreased renin concentration was maintained after administration of L-NAME, except during the late-onset of treatment.

It could be concluded that in experimental rats with renovascular hypertension the vasodilatatory effect of palosuran outweighs the inhibitory effect of L-NAME on NO production and urotensin-induced endothelium-independent vasoconstrictive effect, especially at the early stages and early onset of treatment of hypertension. Palosuran might represent a new therapeutic option in individuals with hypertension disease.


Keywords


Renovascular hypertension, urotensin-II receptors, renin, palosuran, L-NAME.

Full Text:

PDF

References


Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513–1518;

Hypertension Research 2014;37:279–285;

Burnier M., Kjeldsen S., Heagerty A., Williams B. Drug treatment of hypertension Oxford Medicine Online https://oxfordmedicine.com/view/10.1093/med/9780198784906.001.0001/med-9780198784906-chapter-569;

Podzolkov V., Tarzimanova A., Georgadze Z. Modern Principles of Treatment of Uncontrolled Hypertension. Rational Pharmacotherapy in Cardiology Home. 2019; 15(5): 736-741;

Suguro T, Watanabe T, Ban Y, et al. Increased human urotensin II levels are correlated with carotid atherosclerosis in essential hypertension. Am J Hypertens. 2007 Feb; 20(2):211-7;

Totsune K, Takahashi K, Arihara Z, et al. Elevated plasma levels of immunoreactive urotensin II and its increased urinary excretion in patients with Type 2 diabetes mellitus: association with progress of diabetic nephropathy. Peptides. 2004 Oct; 25(10):1809-14;

Bousette N., Hu F., Ohlstein E. H., Dhanak D., Douglas S. A., Giaid A. Urotensin-II blockade with SB-611812 attenuates cardiac dysfunction in a rat model of coronary artery ligation. J. Mol. Cell. (2006). Cardiol. 41, 285–29510.1016/j.yjmcc.2006.05.008;

Desai N, Sajjad J, Frishman WH. Urotensin II: a new pharmacologic target in the treatment of cardiovascular disease. Cardiol Rev. 2008 May-Jun; 16(3):142-53;

Suguro T, Watanabe T, Ban Y, et al. Increased human urotensin II levels are correlated with carotid atherosclerosis in essential hypertension. Am J Hypertens. 2007 Feb; 20(2):211-7;

Douglas SA, Ohlstein EH. Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease., Trends Cardiovasc Med. 2000 Aug; 10(6):229-37;

Gardiner SM, March JE, Kemp PA, et al. Regional heterogeneity in the haemodynamic responses to urotensin II infusion in relation to UT receptor localisation.J Pharmacol. 2006 Mar; 147(6):612-21;

Lapp H, Boerrigter G, Costello-Boerrigter LC, et al. Elevated plasma human urotensin-II-like immunoreactivity in ischemic cardiomyopathy.Int J Cardiol. 2004 Mar; 94(1):93-7;

Bottrill FE, Douglas SA, Hiley CR, White R, Br. Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries. J Pharmacol. 2000 Aug; 130(8):1865-70;

Matsushita M, Shichiri M, Imai T, et al. Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens. 2001 Dec; 19(12):2185-90;

Maguire JJ, Davenport AP. Is urotensin-II the new endothelin? Br J Pharmacol 137: 579–588, 2002;

Douglas S. A., Dhanak D., Johns D. G. From “gills to pills”: urotensin-II as a regulator of mammalian cardiorenal function. Trends Pharmacol. Sci. 2004; 25:76–8510.1016/j.tips.2003.12.005.

Sondermeijer B., Komp A., Komesaroff P., Krum H. Effects of exogenous urotensin-II on vascular tone in skin microcirculation of patients with essential hypertension. Am.J. Hypertens. 2005; 22:1341–1344

Lim et al., 2004 Lim M., Honisett S., Sparkes C. D., Komesaroff P., Kompa A., Krum H. Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation. 2004; 109, 1212–1214;

American Journal of Hypertension. Am J Hypertens 2007;20: 211–217;

Lim M, Honisett S, Sparkes CD, et al. Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation. 2004 Mar 16; 109(10):1212-4;

Clozel M, Hess P, Qiu C, Ding SS, Rey M J.The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats. Pharmacol Exp Ther. 2006 Mar; 316(3):1115-21;

Pehlivan Y, Turkbeyler IH, et al. Urotensin inhibition with palosuran could be a promising alternative in pulmonary arterial hypertension. Onat AM1, Hypertension. 2010; 55 (5):1206-9;

Sidharta PN, Wagner FD, Bohnemeier H, et al. Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients. Clin Pharmacol Ther. 2006 Sep; 80(3):246-56;

Vogt L1, Chiurchiu C, Chadha-Boreham H. et al. Effect of the urotensin receptor antagonist palosuran in hypertensive patients.Trends Pharmacol Sci. 2004 Feb; 25(2):76-85;

Clozel M, Binkert C, Birker-Robaczewska M, et al. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther. 2004; 311: 204–212;

Clozel M, Hess P, Qiu C, Ding SS, Rey M. The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats. J Pharmacol Exp Ther. 2006; 316: 1115–1121;

Goldblatt P. The Goldblatt experiment: a conceptual paradigm. In: Hypertension: Pathophysiology, Diagnosis and Management, edited by J. H. Laragh and B. M. Brenner. New York: Raven, 1995; pp. 23–35;

Mitchell K., Navar L.. Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension. In: Hypertension: Pathophysiology, Diagnosis, and Management, edited by J. H. Laragh and B. M. Brenner. New York: Raven, 1995, pp.1437–1450;

Ploth D. Angiotensin-dependent renal mechanisms in two-kidney one-clip renal vascular hypertension. Am. J. Physiol. 245 (Renal Fluid Electrolyte Physiol. 14): F131–F141, 1983).

Ishihata A, Ogaki T, Aita T, Katano Y. Role of prostaglandins in urotensin II-induced vasodilatation in the coronary arteries of aged rats. Eur J Pharmacol 523: 119–126, 2005;

Lin L., Ding WH., Jiang W., Zhang YG., Qi YF., Yuan WJ., Tang CS. Urotensin-II activates L-arginine/nitric oxide pathway in isolated rat aortic adventitia. Peptides 25: 1977–1984, 2004;

Katano Y, Ishihata A, Aita T, Ogaki T, Horie T. Vasodilator effect of urotensin II, one of the most potent vasoconstricting factors, on rat coronary arteries. Eur J Pharmacol 402: 209–211, 2000;

Gibson A. Complex effects of Gillichthys urotensin II on rat aortic strips. Br J Pharmacol 91: 205–212, 1987;

Kimiko Ishiguro, Hiroyuki Sasamura, Yusuke Sakamaki, Hiroshi Itoh, Takao Saruta. Developmental Activity of the Renin-Angiotensin System during the “Critical Period” Modulates Later L-NAME–Induced Hypertension and Renal Injury. Hypertension Research. 2007, p.30–75;

Liffert Vogt, Carlos Chiurchiu, Harbajan Chadha-Boreham, et al. Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy. Hypertension. 2010;55:1206-1209;

Wendy J. Bottinor, Megan M. Shuey, Ali Manouchehri, et al. Renin-Angiotensin-Aldosterone System Modulates Blood Pressure Response During Vascular Endothelial Growth Factor Receptor Inhibition. JACC: CARDIOONCOLOGY, 2019;1(1); http://creativecommons.org/licenses/by-nc-nd/4.0/;

Marisa K. Ames, Clarke E. Atkins, Bertram Pitt. The renin‐angiotensin‐aldosterone system and its suppression. J Vet Intern Med. 2019;33(2):




DOI: http://dx.doi.org/10.52155/ijpsat.v26.1.2947

Refbacks

  • There are currently no refbacks.


Copyright (c) 2021 Ketevan Ghambashidze

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.