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Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. [ABSTRACT FROM AUTHOR]

Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to downregulate the renin-angiotensin system. PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain renin-angiotensin system activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR-γ expression in the paraventricular nucleus of hypothalamus, an important cardiovascular region, was unchanged in HF compared with sham-operated rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-κB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater; plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased; and maximal left ventricular dP/dt was decreased. All of these findings were ameliorated in HF rats treated with intracerebroventricular pioglitazone, which increased PPAR-γ expression and DNA binding activity in the paraventricular nucleus of hypothalamus. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction-induced HF. [ABSTRACT FROM AUTHOR]

Inflammation is associated with increased sympathetic drive in cardiovascular diseases. Blood-borne proinflammatory cytokines, markers of inflammation, induce cyclooxygenase 2 (COX-2) activity in perivascular macrophages of the blood-brain barrier. COX-2 generates prostaglandin E(2), which may enter the brain and increase sympathetic nerve activity. We examined the contribution of this mechanism to augmented sympathetic drive in rats after myocardial infarction (MI). Approximately 24 hours after acute MI, rats received an intracerebroventricular injection (1 microL/min over 40 minutes) of clodronate liposomes (MI+CLOD) to eliminate brain perivascular macrophages, liposomes alone, or artificial cerebrospinal fluid. A week later, COX-2 immunoreactivity in perivascular macrophages and COX-2 mRNA and protein had increased in hypothalamic paraventricular nucleus of MI rats treated with artificial cerebrospinal fluid or liposomes alone compared with sham-operated rats. In MI+CLOD rats, neither perivascular macrophages nor COX-2 immunoreactivity was seen in the paraventricular nucleus, and COX-2 mRNA and protein levels were similar to those in sham-operated rats. Prostaglandin E(2) in cerebrospinal fluid, paraventricular nucleus neuronal excitation, and plasma norepinephrine were less in MI+CLOD rats than in MI rats treated with artificial cerebrospinal fluid or liposomes alone but more than in sham-operated rats. Intracerebroventricular CLOD had no effect on interleukin 1beta and tumor necrosis factor-alpha mRNA and protein in the paraventricular nucleus or plasma interleukin-1beta and tumor necrosis factor-alpha, which were increased in MI compared with sham-operated rats. In normal rats, pretreatment with intracerebroventricular CLOD reduced (P<0.05) the renal sympathetic, blood pressure, and heart rate responses to intracarotid artery injection of tumor necrosis factor-alpha (0.5 microg/kg); intracerebroventricular liposomes had no effect. The results suggest that proinflammatory cytokines stimulate sympathetic excitation after MI by inducing COX-2 activity and prostaglandin E(2) production in perivascular macrophages of the blood-brain barrier. [ABSTRACT FROM AUTHOR]

Blood-borne tumor necrosis factor (TNF)-α acts upon the central nervous system to augment sympathetic drive in normal and pathophysiological conditions including heart failure. We have found that brain extracellular signal-regulated kinase (ERK)1/2 mediates TNF-α induced sympatho-excitatory responses, but the precise mechanisms are not understood. ERK1/2 can rapidly phosphorylate the voltage gated potassium channel (Kv) subunit Kv4.2 in neurons to reduce the transient outward potassium current that normally restrains neuronal excitability in cardiovascular-related brain regions. We hypothesized that ERK1/2 phosphorylation of Kv4.2 in the hypothalamic paraventricular nucleus (PVN) may contribute to TNF-α-induced sympathetic activity. In anesthetized rats, a centrally directed intracarotid artery (ICA) injection of TNF-α (0.5 μg/kg) increased (∗p<0.05, vs baseline) renal sympathetic nerve activity, mean blood pressure and heart rate beginning as early as 30 minutes. These responses were reduced by a 4-hour continuous intracerebroventricular (ICV) infusion of the ERK1/2 inhibitor PD98059 (0.4 μg/hour). Molecular studies revealed that TNF-α-induced phosphorylation of ERK1/2 and Kv4.2 was detectable at 30 minutes (0.51±0.03∗ vs 0.28±0.03 for ERK1/2, 0.19±0.02∗ vs 0.00±0.00 for Kv4.2, TNF-α vs control, corrected by β-actin) and increased with time (4 hours after TNF-α: 0.65±0.01∗ vs 0.25±0.04 for ERK1/2; 0.30±0.02∗ vs 0.00±0.00 for Kv4.2). Interestingly, mRNA expression for nuclear factor (NF)-κB p65 or its inhibitor IκBα was unchanged at 30 minutes. However, 4 hours after TNF-α injection NF-κB p65 mRNA (1.77±0.11∗ vs 1.00±0.02 fold change) was augmented and IκBα mRNA (0.48±0.03∗ vs 1.00±0.07 fold change) was decreased. ICV PD98059 normalized phosphorylation of ERK1/2 (0.30±0.01∗) and reduced phosphorylation of Kv4.2 (0.16±0.02∗) as well as activation of NF-κB (1.34±0.11∗ for NF-κB p65; 0.70±0.08∗ for IκBα) in the PVN 4 hours after TNF-α injection. These data suggest that the acute sympatho-excitatory responses elicited by blood-borne TNF-α are mediated, at least in part, by brain ERK1/2-induced phosphorylation of Kv4.2, reducing the transient outward potassium current and increasing neuronal excitation. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is characterized by increased sympathetic nerve activity, driven in part by increases in brain inflammation and renin-angiotensin system activity. Angiotensin II (ANG II) and pro-inflammatory cytokines (PICs) activate neuronal MAPK signaling, which has been implicated in sympathetic activation in HF. ANG II and PICs can also activate ER stress, which plays an important role in regulating sympathetic drive and cardiovascular function in ANG II hypertension. The present study was designed to determine whether ER stress occurs in cardiovascular regions of the brain in HF, and if so how MAPK signaling interacts with ER stress. HF and SHAM (n=6) rats were produced by coronary ligation or sham ligation, respectively. HF rats received a chronic (4 wk) intracerebroventricular (ICV) infusion (0.25 μl/hr) of vehicle (Veh, n=6) or an inhibitor (0.25μg/μl, n=6 in each group) selective for p44/42 MAPK (PD98059), JNK (SP600125), or p38 MAPK (SB203580). ER stress markers (GRP78, ATF-6, P58IPK and CHOP) and NF-κB components (NF-κB p65 and IκB-α) were measured in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) by real time PCR. Plasma norepinephrine (NE) was measured by ELISA. Compared with SHAM rats, Veh-treated HF rats had significantly (∗p<0.05) higher mRNA levels for the ER stress markers in SFO (2-3 folds) and PVN (1.8-2.5 folds); these levels were lower (28-55%∗) in the HF rats treated with the MAPK inhibitors, with SB203580 being most effective in SFO and PD98059 most effective in PVN. Veh-treated HF rats had higher (95 ± 11 %∗) NF-κB p65 mRNA level and lower (46 ± 5 %∗) IκB-α mRNA level in SFO and PVN, compared with SHAM rats; these indicators of increased inflammation did not occur in the HF rats treated with the MAPK inhibitors. The plasma NE level (ng/ml) was higher in Veh-treated HF (36.93 ± 2.60∗) than SHAM (17.90 ± 2.59) rats; this increase was attenuated in the HF rats treated with PD98059 (13.64 ± 0.92∗) and SB203580 (24.68 ± 2.71∗). These data demonstrate that ER stress increases in the SFO and PVN of rats with ischemia-induced HF. Inhibition of brain MAPK signaling reduces brain ER stress and inflammation and decreases sympathetic excitation in HF. Brain MAPK signaling is a potential target for therapeutic intervention in HF. [ABSTRACT FROM AUTHOR]

Introduction: Epidermal growth factor receptor (EGFR) and c-Src tyrosine kinase mediate multiple functions of aldosterone and angiotensin II in peripheral cardiovascular tissues by regulating mitogen-activated protein kinase (MAPK) signaling. Hypothesis: EGFR and c-Src activity in cardiovascular regions of the brain contribute to sympatho-excitatory responses induced by circulating aldosterone.METHODS: In anesthetized rats, we recorded renal sympathetic nerve activity (RSNA), mean blood pressure (MBP) and heart rate (HR) at baseline and for 4 hours during intravenous infusion of aldosterone (30 μg/hr), with or without concomitant intracerebroventricular (ICV) infusion of the EGFR inhibitor AG1478 (1 nmol/hr), the mineralocorticoid receptor (MR) antagonist RU28318 (10 μg/hr) or the p44/42 MAPK inhibitor PD98059 (5 μg/hr), or pretreatment with a bolus ICV injection of the c-Src inhibitor SU6656 (1 nmol). In some rats, hypothalamic paraventricular nucleus (PVN) tissues were collected to examine the expression of phosphorylated p44/42 MAPK.Results: Aldosterone infusion significantly (∗p<0.05 vs baseline) increased RSNA (25.3 ± 4.6 %∗), MBP (9.8 ± 2.2 mmHg∗) and HR (28.2 ± 6.2 bpm∗), as well as the PVN expression of phosphorylated p44/42 MAPK (86%, p<0.05), as compared with vehicle. Concomitant ICV infusion of the EGFR inhibitor AG1478 significantly (†p<0.05 vs aldosterone alone) diminished the phosphorylation of p44/42 MAPK (28 %†) in PVN and the increases in RSNA (3.6 ± 1.5 %†), MBP (3.2 ± 1.3 mmHg†) and HR (5.3 ± 5.1 bpm†) induced by aldosterone. ICV pretreatment with the c-Src inhibitor SU6656 had similar significant (p<0.05) inhibitory effects on the RSNA, MBP and HR responses to aldosterone. Concomitant ICV infusion of either the MR antagonist RU28318 or the p44/42 MAPK inhibitor PD98059 prevented the aldosterone-induced sympathetic excitation.Conclusion: Central inhibition of EGFR and c-Src significantly reduced the brain MR- and MAPK-dependent sympathetic excitation elicited by systemically administered aldosterone. Brain EGFR and c-Src are potential therapeutic targets for cardiovascular disease states characterized by high circulating levels of aldosterone. [ABSTRACT FROM AUTHOR]

Introduction: Pro-inflammatory cytokines (PIC) play an important role in regulating autonomic and cardiovascular function in hypertension (HTN) and heart failure (HF). Peripherally administered PIC such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) act within the brain to increase blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA). These molecules are too big to cross blood brain barrier (BBB), and so the mechanisms by which they activate sympathetic drive to elicit hemodynamic responses remain quite a mystery. Our preliminary data indicate a dense distribution of TNF-α and IL-1β receptors in the subfornical organ (SFO), a forebrain which lacks a BBB and can be accessed readily by circulating PIC. The SFO projects to the hypothalamic paraventricular nucleus, which has been implicated as an important source of cardiovascular and autonomic dysfunction in HTN and HF.Hypothesis: SFO neurons sense circulating PIC and mediate their effects on sympathetic drive and hemodynamic responses.Methods: One week after an SFO lesion or a sham lesion (SHAM), urethane anesthetized male SD rats underwent an intracarotid artery (ICA) injection of TNF-α (200 ng) or IL-1β (200 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were recorded.Results: In SHAM rats (n=5), ICA TNF-α dramatically increased (∗ p<0.05 vs. baseline) the BP (23 ± 1.5∗), HR (61 ± 5∗) and RSNA (88.5 ± 4.3 %∗) responses, which peaked ∼30 min after injection. These early excitatory responses to ICA TNF-α were absent in SFO-lesioned rats (n=5), though a moderate excitatory response occurred hours later. Similarly, ICA IL-1β elicited increases in BP (21.8 ± 2.1∗), HR (62 ± 6∗) and RSNA (116.5 ± 5.2∗) in the SHAM rats (n=5). In the SFO-lesioned rats (n=5), the BP (8.6 ± 1.3 †), HR (24 ± 2 †) and RSNA (26.8 ± 1.6 †) responses to ICA IL-1β were significantly († <0.05 vs. SHAM) attenuated.Conclusion: These data suggest that the SFO plays an important role as a central nervous system sensor of the peripheral inflammatory state, mediating the effects of circulating PIC on sympathetic drive and cardiovascular function in inflammatory conditions such as HTN and HF. The later occurring excitatory responses to PIC are unexplained but may involve their known vascular effects. [ABSTRACT FROM AUTHOR]

Upregulation of inflammation and renin-angiotensin system (RAS) activity in the brain contributes to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. Peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, is expressed in key brain areas involved in drinking, vasopressin release and cardiovascular regulation, including the paraventricular nucleus of hypothalamus (PVN). We recently reported that activation of brain PPAR-γ reduced inflammation and RAS activity in the PVN and ameliorated the peripheral manifestations of heart failure. Here we hypothesized that activation of central PPAR-γ might have beneficial effects on angiotensin II (ANG II)-induced hypertension. Spague-Dawley rats received a continuous 2 week subcutaneous infusion of ANG II (120 ng/kg/min), combined with intracerebroventricular infusion of vehicle (VEH) or the PPAR-γ agonist pioglitazone (3 nmoL/h). At 2 weeks, blood pressure (BP) had significantly (∗P<0.05) increased (131±3∗ vs 98±3 mmHg) and the BP response to ganglionic blockade (70±4∗ vs 43±3 mmHg) was greater in conscious VEH-treated ANG II rats compared with normal (control) rats. Water intake (34±2∗ vs 25±2 mL) and plasma vasopressin following 4 hours of water restriction (20.79±2.62∗ vs 10.62±1.27 pg/mL) were increased. PPAR-γ mRNA in the PVN was unchanged in VEH-treated ANG II rats, compared with control rats, but PPAR-γ DNA binding activity (0.05±0.01∗ vs 0.09±0.01 OD450nm) was reduced and mRNA for interleukin-1β (2.76±0.22∗ vs 1.09±0.21 fold change), tumor necrosis factor-α (1.58±0.09∗ vs 1.04±0.12 fold change) and ANG II type-1 receptor (1.71±0.15∗ vs 1.03±0.10 fold change) was augmented. All of these findings were ameliorated (by 24-36%∗) in ANG II rats treated with pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in the PVN (by 73-77%∗). The results suggest that activating brain PPAR-γ to reduce central inflammation and RAS activity, thereby suppressing fluid intake, vasopressin release and sympathetic drive, may be a novel approach to the treatment of ANG II-dependent hypertension. [ABSTRACT FROM AUTHOR]