In chronic heart failure (CHF), an overactive skeletal muscle exercise pressor reflex (EPR) results in excessive sympatho‐excitation and exercise intolerance. However, the mechanism(s) of the exaggerated EPR in CHF state remains to be determined. We recently found that muscle NADPH oxidase‐derived reactive oxygen species (ROS) plays an excitatory role in modulation of EPR function in normal rats. In this study, we used the technique of in vivo siRNA to selectively knockdown the protein expression of p22phox (a NADPH oxidase subunit) in hindlimb muscles of CHF rats in order to investigate the contribution of NADPH oxidase‐derived ROS to the exaggerated EPR in CHF. Data from western blotting and immunofluorescence experiments showed that compared with sham rats, the protein expression of p22phox in triceps surae muscle was significantly increased in CHF rats (ratio of p22phox to GAPDH: 0.32±0.03 vs. 0.15±0.02, CHF vs. Sham, n=5, P<0.05). Silencing p22phox in skeletal muscle with in vivo siRNA (1 week) dramatically decreased the protein expression by almost 70% in CHF rats. Animal experiments showed that gene silencing of p22phox in hindlimb muscles significantly attenuated the EPR‐evoked pressor response to a 30‐s static contraction induced by electrical stimulation of L4/L5 ventral roots in CHF rats (+33.1±2.8 vs. +20.8±1.5 mmHg, CHF vs. CHF+siRNA, n=5, P<0.05) whereas treatment with control siRNA has no effect on the EPR function. These data suggest that elevated muscle NADPH oxidase‐derived ROS contributes to the exaggerated EPR in the CHF state.
SCAP has a protective effect on ethanol-induced liver injury in mice and cells, and the mechanism underlying may be via inhibiting the expression of CYP2E1 protein and then alleviating oxidative stress injury induced by ethanol.
Muscle metabolic by-products during exercise, such as K+, lactic acid, ATP, H+, and phosphate, are well established to be involved in the reflex cardiovascular response to static muscle contraction. However, the role of muscle reactive oxygen species (ROS), a metabolic by-product during muscle contraction, in the exercise pressor reflex (EPR) has not been investigated in detail. In the present study, we evaluated the role of muscle ROS in the EPR in a decerebrate rat model. We hypothesized that muscle NADPH oxidase-derived ROS contributes to sensitization of the EPR. Thus the rise in blood pressure and heart rate in response to a 30-s static contraction induced by electrical stimulation of L4/L5 ventral roots was compared before and after hindlimb arterial infusion of the redox agents: diethyldithiocarbamate, a superoxide dismutase inhibitor; the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine 1-oxyl (tempol); the free radical scavenger dimethylthiourea; a NADPH oxidase inhibitor, apocynin; and a xanthine oxidase inhibitor, allopurinol. The EPR-induced pressor response was augmented after treatment with diethyldithiocarbamate and was attenuated after treatment with tempol, dimethylthiourea, and apocynin. Treatment with allopurinol did not affect the EPR function. None of the drug's affected the EPR heart rate response. In addition, neither the pressor response to electrical stimulation of the central end of dorsal roots, nor femoral blood flow was affected by any treatment. These data suggest that NADPH oxidase-derived muscle ROS plays an excitatory role in the EPR control of blood pressure.
The cardiac "sympathetic afferent" reflex (CSAR) has been reported to increase sympathetic outflow and depress baroreflex function via a central angiotensin II (ANG II) mechanism. In the present study, we examined the role of ANG II type 1 (AT(1)) receptors in the nucleus tractus solitarii (NTS) in mediating the interaction between the CSAR and the baroreflex in anesthetized rats. We examined the effects of bilateral microinjection of AT(1) receptor antagonist losartan (100 pmol) into the NTS on baroreflex control of renal sympathetic nerve activity (RSNA) before and after CSAR activation by epicardial application of capsaicin (0.4 microg). Using single-unit extracellular recording, we further examined the effects of CSAR activation on the barosensitivity of barosensitive NTS neurons and the effects of intravenous losartan (2 mg/kg) on CSAR-induced changes in activity of NTS barosensitive neurons. Bilateral NTS microinjection of losartan significantly attenuated the increases in arterial pressure, heart rate, and RSNA evoked by capsaicin but also markedly (P < 0.01) reversed the CSAR-induced blunted baroreflex control of RSNA (Gain(max) from 1.65 +/- 0.10 to 2.22 +/- 0.11%/mmHg). In 17 of 24 (70.8%) NTS barosensitive neurons, CSAR activation significantly (P < 0.01) inhibited the baseline neuronal activity and attenuated the neuronal barosensitivity. In 11 NTS barosensitive neurons, intravenous losartan effectively (P < 0.01) normalized the decreased neuronal barosensitivity induced by CSAR activation. In conclusion, blockade of NTS AT(1) receptors improved the blunted baroreflex during CSAR activation, suggesting that the NTS plays an important role in processing the interaction between the baroreflex and the CSAR via an AT(1) receptor-dependent mechanism.
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