Summary The renin-angiotensin system (RAS), in addition to its endocrine functions, plays a role within individual tissues such as the brain. The brain RAS is thought to control blood pressure through effects on fluid intake, vasopressin release and sympathetic nerve activity (SNA), and may regulate metabolism through mechanisms which remain undefined. We used a double-transgenic mouse model that exhibits brain-specific RAS activity to examine mechanisms contributing to fluid and energy homeostasis. The mice exhibit high fluid turnover through increased adrenal steroids, which is corrected by adrenalectomy and attenuated by mineralocorticoid receptor blockade. They are also hyperphagic but lean because of a marked increase in body temperature and metabolic rate, mediated by increased SNA and suppression of the circulating RAS. β-adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure.

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BACKGROUND AND PURPOSE:Voxel size/shape of diffusion tensor imaging (DTI) may directly affect the measurement of fractional anisotropy (FA) in regions where there are crossing fibers. The purpose of this article was to investigate the effect of voxel size/shape on measured FA by using isotropic and nonisotropic voxels.

. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II-like immunoreactivity was markedly increased in the subfornical organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGT flox ), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGT flox by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRA flox mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.

Abstract-The role of nitric oxide (NO) in the brain in the control of blood pressure and the sympathetic nervous system is debated. This study examined the effect of overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarii (NTS) on blood pressure in conscious rats. Adenovirus vectors encoding either eNOS (AdeNOS) or ␤-galactosidase were transfected into the NTS in vivo. In the AdeNOS-treated rats, the local expression of eNOS in the NTS was confirmed by immunohistochemical staining and Western blot analysis for the eNOS protein and by increased production of nitrite/nitrate in the NTS measured by in vivo microdialysis. Blood pressure and heart rate, monitored by the use of a radiotelemetry system in a conscious state, were significantly decreased in the AdeNOS-treated group at day 5 to day 10 after the gene transfer. Urinary norepinephrine excretion also was decreased at day 7 after the gene transfer in the AdeNOS-treated group. Our results indicate that overexpression of eNOS in the NTS decreases blood pressure, heart rate, and sympathetic nerve activity in conscious rats. (Hypertension. 2000;36:1023-1028.)Key Words: genes Ⅲ nitric oxide Ⅲ brain Ⅲ sympathetic nervous system T here is considerable evidence that nitric oxide (NO) in the brain affects sympathetic nerve activity and modulates blood pressure and heart rate. [1][2][3][4][5][6] Studies that used immunohistochemistry for neuronal NO synthase (nNOS), nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining, have demonstrated the presence of nNOS at a high concentration in the regions of the brain stem, such as the nucleus tractus solitarii (NTS) and the ventrolateral medulla (VLM), which plays an important role in regulation of sympathetic nerve activity. 7,8 However, conflicting results have been obtained with regard to the effect of NO in the regulation of blood pressure and sympathetic nerve activity. Several studies have demonstrated that unilateral microinjection of the NOS inhibitor N G -monomethyl-L-arginine (L-NMMA) into the NTS produced the pressor effect, 1,2 and L-arginine, the precursor of NO, decreased blood pressure, heart rate, and renal sympathetic nerve activity. 2 On the contrary, the other study has shown that the microinjection of N -nitro-L-arginine methyl ester (L-NAME), another NOS inhibitor, into the NTS decreased blood pressure, heart rate, and renal sympathetic nerve activity, 3 and the NO donor Et 2 N[N(O)NO]Na (NOC 18) increased those variables. 3 Similarly, conflicting results have also been reported as regard to the effects of NO in the rostral VLM. 2,4,5 However, all of these studies were performed in anesthetized animals and examined only acute effects of NO or NOS inhibitors. Long-term effects of increased NO production in these regions on the regulation of blood pressure and sympathetic nerve activity in conscious animals remain to be clarified.Replicant-deficient recombinant adenovirus is now widely used for gene transfer into the brain as well as into the blood vessel. 9 -12 Of...