Abstract-Accumulating evidence indicates a key role of inflammation in hypertension and cardiovascular disorders. However, the role of inflammatory processes in neurogenic hypertension remains to be determined. Thus, our objective in the present study was to test the hypothesis that activation of microglial cells and the generation of proinflammatory cytokines in the paraventricular nucleus (PVN) contribute to neurogenic hypertension. Intracerebroventricular infusion of minocycline, an anti-inflammatory antibiotic, caused a significant attenuation of mean arterial pressure, cardiac hypertrophy, and plasma norepinephrine induced by chronic angiotensin II infusion. This was associated with decreases in the numbers of activated microglia and mRNAs for interleukin (IL) 1␤, IL-6, and tumor necrosis factor-␣, and an increase in the mRNA for IL-10 in the PVN. Overexpression of IL-10 induced by recombinant adenoassociated virus-mediated gene transfer in the PVN mimicked the antihypertensive effects of minocycline. Furthermore, acute application of a proinflammatory cytokine, IL-1␤, into the left ventricle or the PVN in normal rats resulted in a significant increase in mean arterial pressure. Collectively, this indicates that angiotensin II induced hypertension involves activation of microglia and increases in proinflammatory cytokines in the PVN. These data have significant implications on the development of innovative therapeutic strategies for the control of neurogenic hypertension. (Hypertension. 2010;56:297-303.)Key Words: angiotensin II Ⅲ hypertension Ⅲ minocycline Ⅲ interleukin 10 Ⅲ microglia Ⅲ paraventricular nucleus Ⅲ cytokine I nflammation has been implicated in hypertension and cardiovascular diseases in both animal models and human diseases. 1,2 Increases in levels of plasma proinflammatory cytokines (PICs) and other markers of inflammation are associated with the progression of hypertension, whereas immune suppression produces beneficial outcomes. 3,4 Despite evidence for the participation of peripheral cytokines and inflammation in cardiovascular disease, little is known about their involvement in neurogenic hypertension. Studies from Francis and collaborators 5,6 have indicated that angiotensin (Ang) II-induced hypertension involves activation of tumor necrosis factor-␣ (TNF-␣) and nuclear factor B and production of reactive oxygen species in the brain. These observations have led us to propose that Ang II-induced neurogenic hypertension involves activation of microglial cells and production of PICs within the brain. Our objective in the present study was to test this hypothesis.We focused on the paraventricular nucleus (PVN) and a chronic Ang II infusion rat model of hypertension for this study, based on the following rationales. First, the PVN integrates signals/inputs from circumventricular organs and other cardiovascular-relevant brain areas and transmits them to the rostroventrolateral medulla and other downstream areas to influence sympathetic nerve activity. 7 Second, chronic Ang II infusion is an e...

Our observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(1-7)/Mas axis in the treatment of lung disorders.

Rationale: It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.Keywords: renin angiotensin system; angiotensin-converting enzyme 2; pulmonary heart disease.Pulmonary hypertension (PH) presents a diverse etiology and is defined by a mean pulmonary arterial pressure of greater than 25 mm Hg at rest, or greater than 30 mm Hg with exercise (1). The most common causes of PH include chronic obstructive pulmonary disease (often caused by smoking), left heart failure, substance abuse, schistosomiasis, high altitude exposure, drugs, toxins (e.g., chemical warfare), and HIV infection (2, 3). It has been proposed that these risk factors, coupled with predisposing genetic factors, lead to an imbalance between vasoconstrictor and vasodilator mechanisms. This imbalance initiates a cascade of pathophysiological events in the lungs leading to PH (4). These events are suggested to be set in motion by pulmonary vascular endothelial dysfunction causing enhanced proliferation and activation of lung fibroblasts, leading to extracellular matrix formation and fibrosis, infiltration of inflammatory cells, increased production of proinflammatory cytokines, exaggerated pulmonary vascular remodeling, and smooth muscle hypertrophy (5, 6). Vasodilatory ther...

Abstract-Hypertension is considered a low-grade inflammatory condition induced by various proinflammatory cytokines, including tumor necrosis factor (TNF)-␣. Recent studies have implicated an involvement of TNF-␣ in the development of salt-sensitive hypertension induced by angiotensin II (Ang II). To understand further the relationship between TNF-␣ and Ang II, we examined the responses to Ang II in TNF-␣ knockout (TNF-␣ Ϫ/Ϫ ) mice in the present study. A continuous infusion of Ang II (1 g/kg per minute) for 2 weeks was given to both TNF-␣ Ϫ/Ϫ and wild-type (WT) mice with implanted osmotic minipumps. Daily measurement of water intake, salt intake, and urine output were performed using metabolic cages. Blood pressure was monitored continuously with implanted radiotelemetry. Ang II administration for 2 weeks caused increases in salt (0.2Ϯ0.07 to 5.6Ϯ0.95 mL/d) and water (5.4Ϯ0.34 to 11.5Ϯ1.2 mL/d) intake and in mean arterial pressure (115Ϯ1 to 151Ϯ3 mm Hg) in wild-type mice, but these responses were absent in TNF-␣ Ϫ/Ϫ mice (0.2Ϯ0.04 to 0.3Ϯ0.09 mL/d, 5.5Ϯ0.2 to 6.1Ϯ0.07 mL/d, and 113Ϯ2 to 123Ϯ3 mm Hg, respectively). Cardiac hypertrophy induced by Ang II was significantly attenuated in TNF-␣ Ϫ/Ϫ mice compared with wild-type mice. In a group of TNF-␣ Ϫ/Ϫ mice, when replacement therapy was made with recombinant TNF-␣, Ang II induced similar responses in salt appetite, mean arterial pressure, and cardiac hypertrophy, as observed in wild-type mice. These results suggest that TNF-␣ plays a mechanistic role in mediating chronic Ang II-induced effects on salt appetite and blood pressure, as well as on cardiac hypertrophy.

These findings suggest that an ANG II-induced increase in the brain renin-angiotensin system activates NF-kappaB in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-kappaB activation and neurohumoral excitation in hypertension.