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Chronic heart failure (CHF) is a disease characterized by an overactive sympathetic nervous system. The kidney is especially vulnerable to this adaption and responds with a decrease in mean renal blood flow (MRBF). To assess any possible alpha- 1 adrenergic receptor (A1ADR) mediated contributions to this response we instrumented male New Zealand White rabbits with ventricular pacing leads, surgically removed the renal nerves from one kidney and implanted radiotelemetry to record mean arterial pressure (MAP). To perform these surgeries rabbits were anesthetized with a combination of Ketamine (35 mg/kg), Rompun (5.8 mg/kg) and atropine sulfate (0.01 mg/kg) given IM and followed by Forane gas anesthesia (0.5-3.0%). CHF was induced by rapid ventricular pacing at 380 bpm and validated by echocardiography. Values are means ± S.E.M., compared by an unpaired t-test. In rabbits with CHF (n = 5) we found that removing the renal nerves (n =5) significantly increased MRBF (23.3 ± 3.7 vs. 34.1 ± 2.3, P < .05) at resting MAP compared to rabbits with CHF and intact renal nerves (n = 5). In order to assess contribution of A1ADR stimulation in MRBF control, 100 mg/kg phenylephrine (A1ADR agonist) was infused IV at 0.25 ml/min. At 100 mmHg MRBF in CHF rabbits remained decreased compared to CHF rabbits without renal nerves (13.1 ± 0.9 vs. 21.9 ± 2.3 intact and denervated, respectively, P < 0.5). At the completion of the study the kidneys were removed and native membrane proteins were extracted from cortical tissue. Levels of A1ADR receptor were determined by standard western blot technique. Intact rabbits with CHF expressed significantly higher levels of A1ADR (5.7 ± 1.5; A1ADR/total protein) compared to CHF rabbits without renal nerves (1.8 ± 0.3, P < .05). These data suggest that chronic removal of the renal nerves in animals with CHF contributes to increases in MRBF, in part, by down-regulation of AD1ADR in the kidney. [ABSTRACT FROM AUTHOR]

Chronic Heart Failure (CHF) is a disease characterized by overactivation of the renin-angiotensin system, increased sympathetic outflow, and high oxidative stress. In conditions of high oxidant stress, Nuclear factor erythroid 2 related factor 2 (Nrf2) is dissociated from Kelch-like ECH associated protein 1 (Keap1) to activate antioxidant response element (ARE) genes such as heme oxygenase 1 (HO1) and NQO1 as a compensatory mechanism. p65 nuclear factor kappa B (NF-kB) is one of the primary transcription factors that contributes to the etiology of CHF, recruiting creb binding protein (CBP) to both increase transcription of pro-inflammatory proteins and inhibit transcription of AREs. Exercise training (ExT) has been shown to decrease sympathetic outflow and oxidative stress and improve quality of life in patients with cardiovascular disease, however the mechanism(s) by which ExT is protective remain unclear. The purpose of this study was to investigate the convergence of the Nrf2/Keap1 and NF-kB pathways on CBP in the rostral ventrolateral medulla (RVLM) of the rat brain following CHF and ExT. Animals were anesthetized with isoflourane (0.5-2% in oxygen), intubated and mechanically ventilated. Animals were then infarcted using coronary artery ligation. Following confirmation of CHF by a decrease in ejection fraction using echocardiography, some animals were exercised four weeks post-surgery on a treadmill at a final speed of 25 m/min for 60 minutes, 5 days a week for 6 weeks. Western blot analysis of RVLM micropunches demonstrated that in CHF, there was a significant upregulation in NF-kB and Keap1 proteins compared to sham and a decrease in Nrf2 (n=4-5 per group, p=0.003 for Nrf2 and Keap1, p=0.0016 for NF-kB by unpaired t-test). ExT significantly increased Nrf2 and Keap1 expression compared to both sham and CHF groups but normalized NF-kB expression in CHF animals (n=4-5 per group). Co-immunoprecipitation experiments were then performed to examine the interaction of NF-kB and Nrf2 with CBP. In CHF, there was an increase in NF-kB/CBP interaction and a decrease in Nrf2/CBP association compared to sham (p=0.01 for NF-kB/CBP and Nrf2/CBP by unpaired t-test, n=2). However, during ExT in both sham and CHF groups, there was an increase in Nrf2/CBP interaction and a compensatory decrease in NF-kB/CBP interaction (n=2). Taken together, these data suggest that central Nrf2 is downregulated in CHF and that NF-kB and Nrf2 compete for CBP during CHF and following ExT. [ABSTRACT FROM AUTHOR]