Targeting Hypertension: Superoxide Anions are Involved in Apelin-induced Long-term High Blood Pressure and Sympathetic Activity in the Paraventricular Nucleus

Aim: To determine whether apelin in paraventricular nucleus (PVN) can be a therapeutic target for hypertension. Background: Apelin is a specific endogenous ligand of orphan G protein-coupled receptor APJ. Objective: This study was designed to determine how apelin chronically regulates sympathetic nerve activity and blood pressure in PVN of rats. Methods: Apelin and APJ antagonist F13A were infused into PVN with osmotic minipumps. The NAD(P)H oxidase activity and superoxide anions levels in PVN of rats were determined by chemi-luminescence. Results: Infusion of apelin into PVN of Wistar-Kyoto (WKY) rats induced chronic increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), plasma norepinephrine (NE) level, maximal depressor response to hexamethonium (Hex), NAD(P)H oxidase activity, superoxide anions levels, and Nox4 expression. Infusion of F13A into PVN of spontaneously hypertensive rats (SHRs) caused chronic decreases in SBP, DBP, MAP, plasma NE level, maximal depressor response to Hex, NAD(P)H oxidase activity, and superoxide anions levels. Hex, a sympathetic ganglion blocker, inhibited apelin-induced increases in SBP, DBP and MAP. SOD overexpression in PVN of SHRs inhibited the apelin-induced increase in SBP, DBP, MAP, plasma NE level, and maximal depressor response to Hex. PVN Nox4 knockdown also attenuated the apelin-induced increase in SBP, DBP, MAP, plasma NE level, and maximal depressor response to Hex. Chronic injection of F13A into PVN reduced fibrosis of renal artery, thoracic aorta, and heart in SHRs. Conclusion: These results demonstrated that in PVN apelin induced long-term high blood pressure and sympathetic activity via increasing oxidative stress.