Chronic Intracerebroventricular AT1 Receptor Blockade, but not Renin Inhibition, Normalizes Blood Pressure in (mRen2)27 Transgenic Rats

Young transgenic (mRen2)27 rats (12 wks of age) with mouse Ren2 overexpression exhibit high brain levels of angiotensin (Ang) II that contribute to the mechanism of hypertension. Intracerebroventricular (ICV) Ang‐(1–7) infusion lowers systolic blood pressure (SBP) at this age. To determine whether endogenous Ang‐(1–7) provides a compensatory BP lowering effect in older adult male heterozygous (mRen2)27 rats (28–34 wks of age), we compared ICV infusions of a rat renin inhibitor (10–100 μg/kg/day; n = 7), the AT 1 antagonist candesartan (CV11974; 0.2 mg/kg/day; n = 5), D‐Ala 7 ‐Ang‐(1–7) (DALA, 96 μg/kg/day; n = 6), an Ang‐(1–7) receptor antagonist, or DALA + CV11974 for 4 wks. SBP declined in CV11794 and CV11794 + DALA treated rats in the first wk and remained low throughout (Before vs 4 wks: 182 ± 5 vs 100 ± 7 mm Hg; p < 0.05 and 179 ± 6 vs 118 ± 7 mm Hg; p<0.05, respectively). Neither the renin inhibitor nor DALA altered SBP. That ICV Ang‐(1–7) receptor blockade alone failed to alter SBP and did not reverse the fall in SBP with CV11974 in the (mRen2)27 rats suggests that at this age there is a deficit of endogenous Ang‐(1–7) in brain of hypertensive rats, as seen in older (∼68 wks of age) SD animals. Moreover, AT1 blockade lowers SBP but not the renin inhibitor, suggesting an alternate enzymatic source of brain Ang II contributes to hypertension in these animals. Support: HL‐51952, COSEHC‐Warren Trust