Abstract
Background: Angiotensin II is a potent activator of the Rho-kinase (ROCK) pathway,
through which it exerts some of its adverse vasoconstrictor effects. Clinical evidence on the effects of
blocking the angiotensin II receptor 1 on ROCK activity in hypertensive patients is scarce.
Objective: To demonstrate that ROCK activity in peripheral blood mononuclear cells (PMBCs) in patients
with essential hypertension is reduced earlier than previously observed, along with blood pressure
(BP) lowering on treatment with olmesartan.
Methods: Prospective pilot open study; 17 hypertensive patients were treated with progressive olmesartan
doses starting with 20 mg qd. BP was measured at 3, 6 and 9 weeks after treatment initiation. If
treatment failed to normalize BP after 3 weeks, olmesartan dose was increased to 40 mg qd, and if still
hypertensive after 6 weeks, 12.5 mg of hydrochlorothiazide qd was added. ROCK activity was measured
at baseline and 9 weeks after treatment as myosin phosphatase target subunit 1 phosphorylation
(MYPT1-p/T ratio) in PBMC.
Results: Mean baseline BP was 162 ± 4.9/101 ± 2.4 mmHg. After 9 weeks of treatment, both systolic
and diastolic BP were reduced by 41 and 22 mmHg, respectively (p<0.05). Mean pretreatment MYPT1-
p/T ratio in PMBCs was significantly reduced by 80% after 9 weeks with olmesartan (p<0.01).
Conclusion: Normotension achieved after 9 weeks in 82% of the patients treated with olmesartan was
associated with a significant reduction of ROCK activity in PBMC.
Keywords:
Anti-hypertensive therapy, hypertension, rho kinase, angiotensin II, angiotensin receptor blockers, olmesartan.
Graphical Abstract
[1]
Jalil JE, Lavandero S, Chiong M, et al. Rho/Rho-kinase signal transduction pathway in cardiovascular disease and cardiovascular remodeling. Rev Esp Cardiol 2005; 58: 951-61.
[2]
Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005; 25: 1767-75.
[3]
Shimokawa H, Rashid M. Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci 2007; 28: 296-302.
[4]
Hata T, Soga J, Hidaka T, et al. Calcium channel blocker and Rho-associated kinase activity in patients with hypertension. J Hypertens 2011; 29: 373-9.
[5]
Gabrielli L, Winter JL, Godoy I, et al. Increased Rho kinase activity in hypertensive patients with left ventricular hypertrophy. Am J Hypertens 2014; 27: 838-45.
[6]
Carbone ML, Bregeon J, Devos N, et al. Angiotensin II activates the RhoA exchange factor Arhgef1 in humans. Hypertension 2015; 65: 1273-8.
[7]
Ravarotto V, Pagnin E, Maiolino G, et al. The blocking of angiotensin II type 1receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling. J Renin Angiotensin Aldosterone Syst 2015; 16: 1245-50.
[8]
Rawlings R, Nohria A, Liu PY, et al. Comparison of effects of rosuvastatin (10 mg) versus atorvastatin (40 mg) on rho kinase activity in caucasian men with a previous atherosclerotic event. Am J Cardiol 2009; 103: 437-41.
[9]
Nohria A, Prsic A, Liu PY, et al. Statins inhibit Rho kinase activity in patients with atherosclerosis. Atherosclerosis 2009; 205: 517-21.
[10]
Ocaranza MP, Gabrielli L, Mora I, et al. Markedly increased Rho-kinase activity in circulating leukocytes in patients with chronic heart failure. Am Heart J 2011; 161: 931-7.
[11]
Ocaranza MP, Fierro C, Jalil JE, et al. Rho kinase activation in circulating leukocytes is related to hypertensive myocardial remodeling. Clin Sci (Lond) 2018; 132: 1837-53.
[12]
Fujimura N, Noma K, Hata T, et al. Mineralocorticoid receptor eplerenone improves endothelial function and inhibits Rho-associated kinase activity in patients with hypertension. Clin Pharmacol Ther 2012; 91: 289-97.
[13]
Qiao YN, He WQ, Chen CP, et al. Myosin phosphatase target subunit1(MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure. J Biol Chem 2014; 289: 22512-23.
[14]
Hata T, Goto C, Soga J, et al. Measurement of Rho-associated kinase (ROCK) activity in humans: validity of leukocyte p-MBS/t-MBS in comparison with vascular response to fasudil. Atherosclerosis 2011; 214: 117-21.
[15]
Fierro C, Novoa U, Gonzalez V, et al. Simultaneous Rho kinase inhibition in circulating leukocytes and in cardiovascular tissue in rats with high angiotensin converting enzyme levels. Int J Cardiol 2016; 215: 309-17.
[16]
Kajikawa M, Noma K, Maruhashi T, et al. Rho-associated kinase activity is a predictor of cardiovascular outcomes. Hypertension 2014; 63: 856-64.
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