Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension

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.

Adrenomedullin Attenuates Inflammation in White Adipose Tissue of Obese Rats Through Receptor‐Mediated PKA Pathway

“…Briefly, equal amounts of protein extracts from adipocytes or vWAT were separated by polyacrylamide gel electrophoresis (PAGE) and then were electrotransferred to polyvinylidene difluoride membranes (19 Sigma-Aldrich. LPS, PKA inhibitor P9115, and ADM receptor antagonist ADM22-52 were from Anaspec (Fremont, California).…”

Paraventricular Nucleus Infusion of Oligomeric Proantho Cyanidins Improves Renovascular Hypertension

“…This study found that the production of ROS in the PVN region of hypertensive rats increased, which can enhance sympathetic excitability and promote the progress of hypertension. Chronic administration of tempol, one of oxygen free radical scavengers in the lateral ventricle can attenuate the above changes ( Kang et al, 2019 ). Chronic administration of Nrf2 activator tBHQ via PVN can reduce oxidative stress and inflammatory response in rat PVN region, improve neurotransmitter imbalance in paraventricular nucleus, and reduce sympathetic excitability and blood pressure ( Bai et al, 2017 ).…”

Cardioprotection of Sodium–Glucose Cotransporter 2 Inhibition in Rats With Isoproterenol-Induced Cardiomyopathy

“…Protein expressions of angiotensin II type-1 receptor (AT1R, antibody from Endo Life Science Inc, USA), the superoxide (O 2 -)-generating NADPH oxidase isoforms (NOX2 and NOX4, antibodies from Abcam, Burlingame, CA, USA), and in ammatory markers including TNFα, IL-1β, IL-6 and IL-10 ( antibodies from Proteintech, Chicago, IL, USA) in myocardial tissue were detected by Western blotting [20]. Simply, total cardiac proteins in the homogenate were extracted and measured.…”