Abstract
Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160–180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation.
Highlights
The highly interrelated mechanisms, such as the sympathetic nervous system, renin-angiotensin aldosterone system and oxidative stress play an important role in the development of cardiovascular diseases in obesity, which in turn end in organ damage [1]
There were obvious increases in basal sympathetic nerve activity (SNA), Systolic blood pressure (SBP), and protein expressions of Ang II via type 1 receptor (AT1R) and receptor system calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein 2 (RAMP2)/3 in the paraventricular nucleus (PVN) of obesity-related hypertension (OH) rats, but the endogenous protein expression of IMD in the PVN was much lower in OH rats than in control rats
reactive oxygen species (ROS) derived from NADPH oxidase are closely related to sympathetic overactivation in cardiovascular diseases, such as chronic heart failure and hypertension [24,25]
Summary
The highly interrelated mechanisms, such as the sympathetic nervous system, renin-angiotensin aldosterone system and oxidative stress play an important role in the development of cardiovascular diseases in obesity, which in turn end in organ damage [1]. The neurons within the PVN can be activated by endogenous angiotensin II (Ang II), reactive oxygen species (ROS), glutamate, and so on, which promote sympathetic overdrive and raises BP in rats with diabetes, chronic heart failure or hypertension [6,7,8]. Oxidative stress, such as the increase of NADPH oxidase-dependent ROS resource observed in the PVN contributes to sympathoexcitation and elevated BP [9]. This study was designed to investigate the roles and mechanisms of IMD in the PVN in basal SNA and Ang II-induced sympathetic activation in OH rats
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