Renovascular hypertension in mice with brain-selective overexpression of AT1a receptors is buffered by increased nitric oxide production in the periphery.

Abstract

We recently established a new transgenic mouse model with brain-restricted overexpression of angiotensin II (Ang II) type 1a receptors (NSE-AT(1a)) to unmask the role of the brain renin-angiotensin system in hypertension. To test the hypothesis that these mice would exhibit an early exacerbation of renovascular hypertension, NSE-AT(1a) and nontransgenic (NT) mice underwent 2-kidney-1-clip (2K1C) surgery and blood pressure (BP) and heart rate (HR) were recorded continuously by radiotelemetry for 28 days. Results show that NSE-AT(1a) mice developed hypertension much more rapidly than NT, and this was not attributable to genotype-related differences in plasma or brain Ang II levels. A marked bradycardia accompanied this early increase in BP in NSE-AT(1a) mice, as did a substantial cardiovascular region-specific downregulation of AT(1) receptor binding in brain but not in kidney. As BP reached its plateau in NT ( approximately 1 week after clip), hypertension began to abate and eventually stabilized at significantly lower levels in NSE-AT(1a) mice despite marked elevations in Ang II levels in brain stem and hypothalamus at these later time points. This hypertension reversal and the bradycardia were prevented by chronic infusion of the nitric oxide synthase (NOS) blocker l-NAME. These data, along with evidence showing enhanced NOS expression and NO-mediated compensatory responses in 2K1C NSE-AT(1a) peripheral arteries during this later phase, suggest that activation of endogenous NO systems plays an important role in buffering the maintenance of hypertension caused by overexpression of AT(1a) receptors in the brain.