Oxidative stress is increased in the brain in hypertensive rats, such as spontaneously hypertensive rats (SHR) and stroke-prone SHR. Increased oxidative stress in the brainstem and hypothalamus contributes to the enhanced sympathetic activity thereby leading to hypertension. Overexpression of Mn-SOD in the rostral ventrolateral medulla (RVLM) of the brainstem reduced blood pressure through sympathoinhibition in SHR as well as stroke-prone SHR. In contrast, Mn-SOD overexpression in the paraventricular nucleus (PVN) of the hypothalamus decreased heart rate, but did not decrease blood pressure. Stimulation of the AT1 receptors in the RVLM induced activation of the NAD(P)H oxidase/Rac1 pathway thereby causing reactive oxygen species generation. We found that activities of Ras, p38MAPK, ERK, and caspase-3 in the RVLM were significantly higher in stroke-prone SHR than in age-matched Wistar-Kyoto (WKY) rats. The mitochondrial apoptotic proteins Bax and Bas in the RVLM were also significantly increased in stroke-prone SHR compared with WKY rats. Intracerebroventricular (ICV) infusion of a caspase-3 inhibitor significantly reduced sympathetic activity and improved baroreflex sensitivity in stroke-prone SHR. ICV infusion of an AT1 receptor blocker in stroke-prone SHR inhibited the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. In addition, our findings suggest that excitatory inputs from the PVN are modulated by oxidative stress in the RVLM of SHR. Moreover, we suggest that the decreased numbers of astrocytes in the RVLM are responsible for enhanced sympathetic outflow in stroke-prone SHR because auto-implantation of astrocytes into the RVLM reduced sympathetic activity and blood pressure. Taken together, these findings suggest that AT1 receptor-activated caspase-3 acting through the Ras/p38 MAPK/ERK pathway in the RVLM is critically involved in sympathoexcitation. Thus, AT1 receptors in the RVLM may be an important therapeutic target for hypertension.