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Abstract Background We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model. Methods We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc) and age-matched SD rats.. Blood-pressure- and albuminuria- measurements were monitored during the treatement period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analsis. Results Chronic treatment with the antioxidant PDTC decreased blood pressure (162 ± 8 vs. 190 ± 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 ± 0.1 vs. 5.77 ± 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 ± 0.5 vs. 18.0 ± 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-κB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-κB subunit in the endothelium, smooth muscles cells of damaged small vessels, infiltrated cells, glomeruli, tubuli and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. Conclusion Our data show that inhibition of NF-κB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-κB activation plays an important role in ANG II-induced end-organ damage.

Alterations of the renin-angiotensin system at the RVLM of transgenic rats with low brain angiotensinogen. Am J Physiol Regulatory Integrative Comp Physiol 280: R428-R433, 2001.--The transgenic rats TGR(ASrAOGEN) (TGR) with low levels of brain angiotensinogen were analyzed for cardiovascular reactivity to microinjections of ANG II and angiotensin receptor ([AT.sub.1]) antagonists [CV-11974, [AT.sub.1] specific; A-779, ANG-(1-7) selective; sarthran, nonspecific] into the rostral ventrolateral medulla (RVLM) of conscious rats. Microinjection of ANG II resulted in a significantly higher increase in the mean arterial pressure (MAP) of TGR than control [Sprague-Dawley (SD)] rats, suggesting an upregulation of ANG II receptors in TGR. CV-11974 produced an increase in MAP of SI) but not in TGR rats. A-779 produced a depressor response in SD but not in TGR rats. Conversely, sarthran produced a similar decrease of MAP in both rat groups. The pressor effect of the [AT.sub.1] antagonist may indicate an inhibitory role of [AT.sub.1] receptors in the RVLM. On the other hand, ANG-(1-7) appears to have a tonic excitatory role in this region. The altered response to specific angiotensin antagonists in TGR further supports the functionally relevant decrease in angiotensins in the brains of TGR and corroborates the importance of the central renin-angiotensin system in cardiovascular homeostasis. brain renin-angiotensin system; rostral ventrolateral medulla; blood pressure

Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN). Am J Physiol Regulatory Integrative Comp Physiol 280: R233-R240, 2001.---TGR(ASrAOGEN) 680, a newly developed transgenic rat line with specific downregulation of astroglial synthesis of angiotensinogen, exhibits decreased brain angiotensinogen content associated with a mild diabetes insipidus and lower blood pressure. Autoradiographic experiments were performed on TGR(ASrAOGEN) (TG) and Sprague-Dawley (SD) control rats to quantify [AT.sub.1] and [AT.sub.2] receptor-binding sites in different brain nuclei and circumventricular organs. Dose-response curves for drinking response to intracerebroventricular injections of ANG II were compared between SD and TG rats. In most of the regions inside the blood-brain barrier [paraventricular nucleus (PVN), piriform cortex, lateral olfactory tract (LOT), and lateral preoptic area (LPO)], [AT.sub.1] receptor binding (sensitive to CV-11974) was significantly higher in TG compared with SD. In contrast, in the circumventricular organs investigated [subfornical organ (SFO) and area postrema], [AT.sub.1] receptor binding was significantly lower in TG. [AT.sub.2] receptors (binding sensitive to PD-123319) were detected at similar levels in the inferior olive (IO) of both strains. Angiotensin-binding sites sensitive to both CV-11974 and PD-123319 were detected in the LPO of SD rats and specifically upregulated in LOT, IO, and most notably PVN and SFO of TG. The dose-response curve for water intake after intracerebroventricular injections showed a higher sensitivity to ANG II of TG ([EC.sub.50] = 3.1 ng) compared with SD ([EC.sub.50] = 11.2 ng), strongly suggesting that the upregulation of [AT.sub.1] receptors inside the blood-brain barrier of TG rats is functional. Finally, we showed that downregulation of angiotensinogen synthesized by astroglial cells differentially regulates angiotensin receptor subtypes inside the brain and in circumventricular organs. antisense; angiotensin receptor subtypes

Brain health plays a central role in well-being and in the management of chronic diseases. Stroke and dementia pose the two greatest threats to brain health, but recent developments suggest the possibility that preventing stroke may also prevent some dementias: (a) A large population study showed a 32% decrease in the incidence of stroke and a concomitant 7% reduction in the incidence of dementia; (b) the treatment of atrial fibrillation resulted not only in stroke reduction, but also a 48% decrease in dementia; (c) the hypothesis-free analyses have shown that the first phase of Alzheimer disease involves vascular dysregulation, opening the door to new therapeutic approaches; (d) cognitive impairment, often treatable and reversible, accompanies heart and kidney failure. These developments, combined with the knowledge that stroke, dementia, and heart disease share the same major treatable risk factors, particularly hypertension, offer an opportunity for their joint prevention. This aspiration is expressed by a Proclamation of the World Stroke Organization on Stroke and Potentially Preventable Dementias and endorsed by the World Heart Federation, the World Hypertension League, Alzheimer Disease International, and 18 other international, regional, and national organizations as a call for action. [ABSTRACT FROM AUTHOR]