Injections of angiotensin-converting enzyme 2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats

Abstract

Injections of the angiotensin(1-7) [Ang(1-7)] antagonist [d-Ala7]-Ang(1-7) into the nucleus of the solitary tract (NTS) of Sprague-Dawley rats reduce baroreceptor reflex sensitivity (BRS) for control of heart rate by approximately 40%, whereas injections of the angiotensin II (Ang II) type 1 receptor antagonist candesartan increase BRS by 40% when reflex bradycardia is assessed. The enzyme angiotensin-converting enzyme 2 (ACE2) is known to convert Ang II to Ang(1-7). We report that ACE2 activity, as well as ACE and neprilysin activities, are present in plasma membrane fractions of the dorsomedial medulla of Sprague-Dawley rats. Moreover, we show that BRS for reflex bradycardia is attenuated (1.16 +/- 0.29 ms mmHg-1 before versus 0.33 +/- 0.11 ms mmHg-1 after; P < 0.05; n = 8) 30-60 min following injection of the selective ACE2 inhibitor MLN4760 (12 pmol in 120 nl) into the NTS. These findings support the concept that within the NTS, local synthesis of Ang(1-7) from Ang II is required for normal sensitivity for the baroreflex control of heart rate in response to increases in arterial pressure.