Abstract 558: Role of Angiotensin Converting Enzyme 2/angiotensin (1-7)/mas Axis in the Hypotensive Effect of Azilsartan

Abstract

Objective: The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang (1-7)/Mas axis against the ACE/Ang II/ Ang II type 1 (AT 1 ) receptor axis in blood pressure control has been highlighted. We examined the possibility that this axis might be involved in the anti-hypertensive effect of newly developed Ang II type 1 (AT 1 ) receptor blocker (ARB), azilsartan, in comparison with olmesartan. Methods: Human renin (hRN) and human angiotensinogen (hANG) double transgenic mice (hRN/hANG-Tg) were used. Ten-week-old male hRN/hANG-Tg mice were administrated control chow or three different doses (1, 5 and 10mg/kg/day) of ARBs, azilsartan or olmesartan in chow for 4 weeks. Blood pressure was analyzed by radio telemetry method before drug administration and every two weeks after medication. Four weeks after drug administration, expression of ACE2 mRNA level was assessed by real time RT-PCR method. Results: Blood pressure was significantly higher in hRN/hANG-Tg mice compared with that in wild type (WT) mice. Treatment with all doses of azilsartan decreased blood pressure to the level of WT mice. Treatment with olmesartan (1 mg/kg/day) decreased blood pressure; however, this decrease was weaker than that with azilsartan at the same dose. Olmesartan (5 and 10 mg/kg/day) decreased blood pressure to the WT mice level; however, the reduction of blood pressure in the night-time was stronger in azilsartan group. Expression of ACE2 mRNA was decreased in heart and kidney of hRN/hANG-Tg mice compared with WT mice. This decrease in ACE2 mRNA expression was attenuated by administration of azilsartan, but not by olmesartan treatment. The ratio of heart to body weight ratio was decreased in all azilsartan-treated groups, but this decrease was observed only in 10 mg/kg/day of olmesartan-treated group. Treatment with azilsartan even at lower dose increased the urinary excretion of Na. Conclusion: These results suggested that hypotensive effect of azilsartan may involve the activation of ACE2/Ang(1-7)/Mas axis with AT 1 receptor blockade. Further investigation will reveal the pathophysiological role of ACE2/Ang(1-7)/Mas axis in blood ptessure control and contribute to discuss further the possible drug effect of ARBs beyond class effect.