Background-Oxidative stress increases in hypertension. The aim of this study was to determine whether reactive oxygen species (ROS) are increased in the rostral ventrolateral medulla (RVLM) in the brainstem, where the vasomotor center is located, in stroke-prone spontaneously hypertensive rats (SHRSP), and, if so, to determine whether the increased ROS contribute to neural mechanisms of hypertension in SHRSP. Methods and Results-We measured ROS levels in the RVLM of SHRSP and compared them with those in Wistar-Kyoto rats (WKY). Thiobarbituric acid-reactive substances were increased in SHRSP compared with WKY. ROS were measured by electron spin resonance (ESR) spectroscopy. The ESR signal decay rate in the RVLM of SHRSP was significantly increased compared with that in WKY, and this increase was abolished by dimethylthiourea (a hydroxyl radical scavenger). The increased ESR signal decay rate was reduced to the same extent in the presence of desferrioxamine, catalase, and Tiron, indicating that hydroxyl radicals are derived from superoxide anions and hydrogen peroxide. In addition, total superoxide dismutase (SOD) activity in the RVLM was decreased in SHRSP compared with WKY. Furthermore, bilateral microinjection of tempol into the RVLM decreased blood pressure in SHRSP but not in WKY, and MnSOD overexpression in the RVLM of SHRSP decreased blood pressure and inhibited sympathetic nerve activity. Conclusions-These results suggest that superoxide anions in the RVLM, which generate hydroxyl radicals, are increased in SHRSP and contribute to the neural mechanisms of hypertension in SHRSP.

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In heart failure, it has been recognized that the sympathetic nervous system (SNS) is activated and the imbalance of the activity of the SNS and vagal activity interaction occurs. The abnormal activation of the SNS leads to further worsening of heart failure. Many previous clinical and basic studies have demonstrated that the abnormal activation of the SNS is caused by the enhancement of excitatory inputs including changes in: (1) peripheral baroreceptor and chemoreceptor reflexes; (2) chemical mediators that control sympathetic outflow; and (3) central sites that integrate sympathetic outflow. In particular, the abnormalities in central SNS regulation due to the renin angiotensin system-oxidative stress axis have recently been in focus. In the treatment of heart failure, the inhibition of the activated SNS, such as with beta-blockers and/or exercise training, is important. Furthermore, many experimental studies have demonstrated that vagal stimulation has beneficial effects on heart failure, and recently several clinical studies have also demonstrated that vagal stimulation is a possible novel therapy for heart failure. In conclusion, we must recognize that heart failure is a complex syndrome with an autonomic nervous system dysfunction, and that the autonomic imbalance with the activation of the SNS and the reduction of vagal activity should be treated.

These results indicate that our extracorporeal cardiac shock wave therapy is an effective and non-invasive treatment for end-stage coronary artery disease, although further careful evaluation is needed.