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.
journal_name
Circ Resjournal_title
Circulation researchauthors
Lazartigues E,Lawrence AJ,Lamb FS,Davisson RLdoi
10.1161/01.RES.0000140892.86313.c2subject
Has Abstractpub_date
2004-09-03 00:00:00pages
523-31issue
5eissn
0009-7330issn
1524-4571pii
01.RES.0000140892.86313.c2journal_volume
95pub_type
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