Published online before print July 29, 2004, doi: 10.1161/01.RES.0000140892.86313.c2
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Submitted on March 15, 2004
Revised on June 24, 2004
Accepted on July 20, 2004
Renovascular Hypertension in Mice With Brain-Selective Overexpression of AT1a Receptors Is Buffered by Increased Nitric Oxide Production in the Periphery
Eric Lazartigues ;
From the Departments of Anatomy & Cell Biology (E.L., R.L.D.) and Pediatrics (F.S.L.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; Howard Florey Institute (A.J.L.), University of Melbourne, Victoria, Australia.
* To whom correspondence should be addressed. E-mail: robin-davisson{at}uiowa.edu.
We recently established a new transgenic mouse model with brain-restricted overexpression of angiotensin II (Ang II) nucleus of tractus solitarii type 1a receptors (NSE-AT1a) 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-AT1a 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-AT1a 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-AT1a mice, as did a substantial cardiovascular region-specific downregulation of AT1 receptor binding in brain but not in kidney. As BP reached its plateau in NT (
1 week after clip), hypertension began to abate and eventually stabilized at significantly lower levels in NSE-AT1a 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-AT1a 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 AT1a receptors in the brain.
Key words: renovascular hypertension • nitric oxide • brain • transgenic mice.
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