Central AT1 receptor blockade restores baroreflex sensitivity and lowers blood pressure in ACE2 knockout mice

Abstract

We recently showed the presence of ACE2 in brain regions involved in cardiovascular (CV) regulation. Although angiotensin (Ang)(1-7) is known to increase cardiac baroreflex sensitivity (CBS), the role of ACE2 is unclear. Therefore, we investigated ACE2 role in modulating CBS in ACE2 KO (n=5), exhibiting a high blood pressure (BP) phenotype, and control littermates (n=4). Anesthetized mice were implanted with carotid and jugular catheters for BP and heart rate monitoring and drug infusion, respectively. CBS (bpm/mmHg) was determined following random infusion of phenylephrine (50 ng/min iv) and sodium nitroprusside (5 μg/min iv). In ACE2 KO mice, CBS is significantly altered (−2.8±0.3) compared to control mice (−4.4±0.3; P<0.05) suggesting higher brain Ang-II levels in this model. To confirm the participation of central Ang-II, the experiment was repeated following central blockade of AT1 receptors with Losartan (10 μg/200 nl icv). Although Losartan had no effect on baseline BP in control mice (+1±1 mmHg; P>0.05), it significantly decreased BP in ACE2 KO mice (−11±2 mmHg; P<0.05). Moreover, AT1 receptor blockade partially restored CBS in ACE2 KO mice (−3.3±0.3; P<0.05). These data show that ACE2 is tonically involved in the maintenance of baseline BP and in the central regulation of CV function, offering a new target for the treatment of hypertension and other CV diseases. Support: NIH NS052479 and P20 RR018766