Angiotensin Type 1 Receptors and Superoxide Anion Production in Hypothalamic Paraventricular Nucleus Contribute to Capsaicin-Induced Excitatory Renal Reflex and Sympathetic Activation

Abstract

Chemical stimulation of the kidney increases sympathetic activity and blood pressure in rats. The hypothalamic paraventricular nucleus (PVN) is important in mediating the excitatory renal reflex (ERR). In this study, we examined the role of molecular signaling in the PVN in mediating the capsaicin-induced ERR and sympathetic activation. Bilateral PVN microinjections were performed in rats under anesthesia. The ERR was elicited by infusion of capsaicin into the cortico-medullary border of the right kidney. The reflex was evaluated as the capsaicin-induced changes in left renal sympathetic nerve activity and mean arterial pressure. Blockade of angiotensin type 1 receptors with losartan or inhibition of angiotensin-converting enzyme with captopril in the PVN abolished the capsaicin-induced ERR. Renal infusion of capsaicin significantly increased NAD(P)H oxidase activity and superoxide anion production in the PVN, which were prevented by ipsilateral renal denervation or microinjection of losartan into the PVN. Furthermore, either scavenging of superoxide anions or inhibition of NAD(P)H oxidase in the PVN abolished the capsaicin-induced ERR. We conclude that the ERR induced by renal infusion of capsaicin is mediated by angiotensin type 1 receptor-related NAD(P)H oxidase activation and superoxide anion production within the PVN.

Dysregulation of the Excitatory Renal Reflex in the Sympathetic Activation of Spontaneously Hypertensive Rat

“…Capsaicin stimulates afferents and increases the afferent nerve activity at a low concentration, but causes denervation at a high concentration (Fitzgerald, 1983). The concentration of capsaicin in the present study was used to stimulate the renal afferents and cause ERR (Qiu et al, 2020;Ye et al, 2020;Zheng et al, 2020), which was much lower than the concentration used for denervation in previous studies (Fitzgerald, 1983;Foss et al, 2015). The capsaicin-induced ERR existed in the SHR at the ages of four, 12, and 24 weeks, indicating that the ERR is involved in the sympathetic activation and hypertension from the early stage to the sustained stage of hypertension in SHR.…”

“…Our previous study has shown that the renal infusion of capsaicin dose-dependently induces ERR in normal rats ( Ye et al, 2020 ). The dose of capsaicin at 1 nmol/min for 20 min was selected to induce ERR, and the vehicle for renal infusion had no significant effects on the RSNA, MAP, and HR ( Qiu et al, 2020 ; Ye et al, 2020 ; Zheng et al, 2020 ). At the age of 4 weeks, the early stage with slight or moderate hypertension, unilateral renal infusion of capsaicin caused immediate increases in the contralateral RSNA and MAP in both the WKY and SHR, lasting for at least 30 min.…”

“…Capsaicin, a selective TRPV1 agonist, increases the ipsilateral afferent renal nerve activity in the Wide-type mice but not in the TRPV1 knockout mice ( Zhong et al, 2019 ). Pretreatment with a TRPV1 competitive antagonist capsazepine abolishes the capsaicin-induced ERR ( Qiu et al, 2020 ). These findings indicate that the renal infusion of capsaicin-induced ERR is mediated by the TRPV1 receptors in the kidney.…”

“…Infusion of capsaicin into the upper, lateral, or lower parts of the kidney showed similar ERR effects ( Ye et al, 2020 ). Therefore, the cortico-medullary border of the lateral part of the kidney was selected for the infusion site in inducing ERR ( Qiu et al, 2020 ; Zheng et al, 2020 ). Intravenous infusion of the same dose of capsaicin failed to cause significant effects on the RSNA, mean arterial pressure (MAP), and heart rate (HR), excluding the possibility that the effects of the renal infusion of capsaicin might be caused by leaking into the blood circulation ( Ye et al, 2020 ).…”

“…Recently, we have shown that the chemical stimulation of kidney in normal rats with capsaicin causes an excitatory renal reflex (ERR), which results in the sympathetic activation and pressor responses ( Ye et al, 2020 ). The capsaicin-induced ERR is mediated by angiotensin II in the hypothalamic paraventricular nucleus (PVN), which acts on AT 1 R, and in turn activates NADPH oxidase, causing oxidative stress and the subsequent NFκB activation and IL-1β production in the PVN in normal rats ( Qiu et al, 2020 ; Zheng et al, 2020 ). The renal afferent input increases the activity of some neurons in the PVN ( Xu et al, 2015 ), and destruction of the PVN neurons abolishing the capsaicin-induced ERR ( Ye et al, 2020 ).…”