Abstract
Transgenic (mRen2)27 rats that over express the murine Ren2 gene are hypertensive and have impaired baroreflex sensitivity (BRS) for control of heart rate (HR). We previously showed that infusion of central angiotensin-(1-7) [Ang-(1-7)] improved the vagal components of the BRS independent of altering mean arterial pressure (MAP) but that, AT 1 receptor blockade normalized MAP and blood pressure variability (BPV) without correcting the BRS. To determine if the overall sympathovagal imbalance and the BRS function can be corrected by supplementing Ang-(1-7) in combination with AT 1 receptor blockade, we compared intracerebroventricular (ICV) infusions of the AT 1 receptor antagonist candesartan (CV: 4 ug/5uL/hr) and Ang-(1-7) [0.1 ug/5uL/hr; n = 4] or artificial cerebrospinal fluid (aCSF; 5 uL/hr; n = 8) for 4 weeks in 18 week old male (mRen2)27 rats. MAP was significantly reduced in CV/ Ang-(1-7) treated rats [71 ± 13 vs. aCSF: 132 ± 12 mm Hg; p = 0.01] with no changes in HR. Lowering of MAP was associated with a reduction in low frequency systolic arterial pressure, an index of BPV, [LF-SAP%: 32 ± 8 vs. aCSF: 73 ± 10, p = 0.02] in these animals. Both vagal [high frequency alpha: 1.1 ± 0.3 vs. aCSF: 0.6 ± 0.1, p= 0.05 and Sequence UP: 1.7 ± 0.4 vs. aCSF: 0.7 ± 0.1, p= 0.03] and sympathetic [low frequency alpha: 0.65 ± 0.14 vs. aCSF: 0.34 ± 0.03, p= 0.02 and Sequence DOWN: 1.4 ± 0.3 vs. aCSF: 0.76 ± 0.1, p= 0.01] components of the BRS were significantly increased resulting in improvements in the overall BRS [Sequence ALL: 1.6 ± 0.3 vs. aCSF: 0.75 ± 0.1, p= 0.01] as well as the sympathovagal imbalance [LF RRI /HF RRI : 0.2 ± 0.1 vs. aCSF: 2.3 ± 0.6, p= 0.004] in treated animals. Thus, combination ICV therapy normalized MAP and corrected the sympathovagal imbalance leading to improved BRS function. Since impaired BRS significantly associates with cardiovascular pathologies independently from hypertension, specifically targeting an increase in central Ang-(1-7) with reduced Ang II actions to provide improved BRS and lower MAP may achieve a more optimal therapeutic benefit.
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