Central command dysfunction in rats with heart failure is mediated by brain oxidative stress and normalized by exercise training

Abstract

Key pointsr In heart failure, sympathoexcitation elicited by central command, a parallel activation of the motor and autonomic neural circuits in the brain, is exaggerated.r Mechanisms underlying central command dysfunction in heart failure were unexplored, and effects of exercise training on central command dysfunction in heart failure were not determined.r Data presented here suggest that oxidative stress in the medulla in heart failure mediates central command dysfunction, and that exercise training in heart failure is capable of normalizing central command dysfunction through its antioxidant effects in the medulla.r The present study contributes to our understanding of brain mechanisms underlying abnormal autonomic adjustments to exercise in heart failure.Abstract Sympathoexcitation elicited by central command, a parallel activation of the motor and autonomic neural circuits in the brain, has been shown to become exaggerated in chronic heart failure (CHF). The present study tested the hypotheses that oxidative stress in the medulla in CHF plays a role in exaggerating central command-elicited sympathoexcitation, and that exercise training in CHF suppresses central command-elicited sympathoexcitation through its antioxidant effects in the medulla. In decerebrate rats, central command was activated by electrically stimulating the mesencephalic locomotor region (MLR) after neuromuscular blockade. The MLR stimulation at a current intensity greater than locomotion threshold in rats with CHF after myocardial infarction (MI) evoked larger (P < 0.05) increases in renal sympathetic nerve activity and arterial pressure than in sham-operated healthy rats (Sham) and rats with CHF that had completed longterm (8-12 weeks) exercise training (MI + TR). In the Sham and MI + TR rats, bilateral microinjection of a superoxide dismutase (SOD) mimetic Tempol into the rostral ventrolateral medulla (RVLM) had no effects on MLR stimulation-elicited responses. By contrast, in MI rats, Tempol treatment significantly reduced MLR stimulation-elicited responses. In a subset of MI rats, treatment with Tiron, another SOD mimetic, within the RVLM also reduced responses. Superoxide generation in the RVLM, as evaluated by dihydroethidium staining, was enhanced in MI rats compared with that in Sham and MI + TR rats. Collectively, these results support the study hypotheses. We suggest that oxidative stress in the medulla in CHF mediates central command dysfunction, and that exercise training in CHF is capable of normalizing central command dysfunction through its antioxidant effects in the medulla.

Angiotensin II, Oxidative Stress, and Sympathetic Nervous System Hyperactivity in Heart Failure

“…28 Subsequently, we demonstrated that administration within the RVLM of Tempol, a SOD mimetic, reduced MLR stimulation-elicited sympathoexcitation in CHF, suggesting the role of superoxide overproduction in the RVLM in enhancing central command-elicited sympathetic outflow in CHF. 29 Of note, a recent report by Biancardi et al suggested that circulating AngII plays a role in increasing BBB permeability, thereby facilitating its access to central cardiovascular regions. 30 They found that, the BBB permeability was increased along with downregulated key BBB protein constituents in the PVN and RVLM of spontaneously hypertensive rats that have increased plasma AngII as do CHF animal models.…”

“…47 This effect is likely a result of normalizations of central command and EPR dysfunction. 29,48 We previously demonstrated that the normalization of central command dysfunction in CHF after exercise training was due to its antioxidative effects in the RVLM. 29 Tempol microinjected into the RVLM reduced central command-elicited sympathoexcitation in rats with CHF but had no effect in CHF animals after exercise training.…”

“…29,48 We previously demonstrated that the normalization of central command dysfunction in CHF after exercise training was due to its antioxidative effects in the RVLM. 29 Tempol microinjected into the RVLM reduced central command-elicited sympathoexcitation in rats with CHF but had no effect in CHF animals after exercise training. Moreover, since the EPR becomes exaggerated by AngII-mediated oxidative stress in skeletal muscle, 41 ameliorated RAS overactivation in skeletal muscle after exercise training 49 likely underlies the normalization of the EPR dysfunction in CHF.…”

Exercise-Induced Regulation of Redox Status in Cardiovascular Diseases: The Role of Exercise Training and Detraining

“…Negrao and colleagues [119] reported that only exercise training has been shown to be able to restore the neurohormonal balance and reverse many key features of the skeletal myopathy in patients with HF from systolic dysfunction. In addition, both animal-based research and human studies, have demonstrated that physical exercise is a powerful signal that improves peripheral function in chronic HF and increases the mitochondrial volume and enzyme content, improving the metabolic capacity [119,123,124]. Moreover, regular exercise enhances the endothelial function via an increase in shear stress that promotes nitric oxide synthase (NOS) expression and activity, resulting in more bioavailable NO [123].…”

“…Moreover, regular exercise enhances the endothelial function via an increase in shear stress that promotes nitric oxide synthase (NOS) expression and activity, resulting in more bioavailable NO [123]. Koba et al [124] suggested that oxidative stress in the medulla mediates central command dysfunction, while exercise training in chronic HF is capable of normalizing central command dysfunction through its antioxidant effects in the medulla.…”