Cardiac sympathetic afferent reflex response to intermedin microinjection into paraventricular nucleus is mediated by nitric oxide and γ-amino butyric acid in hypertensive rats

Abstract

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) and involves in the regulation of cardiovascular function in both peripheral tissues and central nervous system (CNS). Paraventricular nucleus (PVN) of hypothalamus is an important site in the control of cardiac sympathetic afferent reflex (CSAR) which participates in sympathetic over-excitation of hypertension. The aim of this study is to investigate whether IMD in the PVN is involved in the inhibition of CSAR and its related mechanism in hypertension. Rats were subjected to two-kidney one-clip (2K1C) surgery to induce renovascular hypertension or sham-operation (Sham). Acute experiments were carried out four weeks later under anesthesia. The CSAR was evaluated with the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to the epicardial application of capsaicin. The RSNA and MAP were recorded in sinoaortic-denervated, cervical-vagotomized and anesthetized rats. Bilateral PVN microinjection of IMD (25 pmol) caused greater decrease in the CSAR in 2K1C rats than in Sham rats, which was prevented by pretreatment with adrenomedullin (AM) receptor antagonist AM22-52, non-selective nitric oxide (NO) synthase (NOS) inhibitor L-NAME or γ-amino butyric acid (GABA)B receptor blocker CGP-35348. PVN pretreatment with CGRP receptor antagonist CGRP8-37 or GABA(A) receptor blocker gabazine had no significant effect on the CSAR response to IMD. AM22-52, L-NAME and CGP-35348 in the PVN could increase CSAR in Sham and 2K1C rats. These data indicate that IMD in the PVN inhibits CSAR via AM receptor, and both NO and GABA in the PVN involve in the effect of IMD on CSAR in Sham and renovascular hypertensive rats.

Superoxide Anions and NO in the Paraventricular Nucleus Modulate the Cardiac Sympathetic Afferent Reflex in Obese Rats

“…In this study, there was an increased O 2 − level and a decreased NO generation in the PVN of OB and OH rats indicating that the changes of O 2 − and NO production may be partially responsible for the enhanced CSAR and sympathetic overdrive during obesity. Previous studies have suggested that PVN O 2 − and NO can participate in the regulation of CSAR in renovascular hypertensive rats [ 8 , 18 , 23 , 30 , 31 ]. In the present study, we indeed observed a greater decrease or increase in CSAR amplitude upon the removal of O 2 − with an analogue of endogenous superoxide dismutase for scavenging O 2 − (PEG-SOD), or by using the superoxide dismutase inhibitor DETC in the PVN in OB and OH rats, respectively.…”

“…These results suggest that O 2 − and NO in the PVN are involved in a tonic excitation or inhibition, respectively, but NO does not exert enough tonic inhibition in the PVN for the enhanced CSAR in obesity, which may be related to the reduced NO level or bioavailability in the PVN. In fact, an imbalance in O 2 − (increase) and NO (decrease) promotes the excitation of the sympathetic nervous system, and this mechanism seems to be involved in the pathogenesis of neurogenic aspects of hypertension [ 8 , 18 , 23 , 30 , 31 ].Therefore, the imbalance of O 2 − and NO generation in the PVN may lead to the enhancement of CSAR contributing to sympathetic overactivity during obesity.…”

“…It is well known that the excessive formation of O 2 − in hypertension may be associated with NADPH oxidase, Ang II, and AT1 receptor. PVN O 2 − produced by Ang II has been indicated to mediate the central Ang II-induced sympathoexcitatory action including CSAR [ 8 , 18 , 23 , 30 , 31 ]. Moreover, NADPH oxidase in PVN could contribute to the effects of Ang II on CSAR, and Ang II, via AT1R, increased NADPH oxidase activity that is responsible for O 2 − generation [ 8 , 18 , 23 , 30 , 31 ].…”

“…The inhibition of neural NO synthase (nNOS) in the PVN elevates the mean arterial pressure (MAP), whereas increasing NO content in the PVN produces depressor responses in normal rats. Moreover, the downregulation of PVN NO was implicated in sympathetic overdrive in rats with hypertension and chronic heart failure (CHF) [ 5 , 22 , 23 , 24 ]. However, the association of O 2 − and NO with CSAR and SNA in obesity has not been evaluated yet.…”

Hexamethonium attenuates sympathetic activity and blood pressure in spontaneously hypertensive rats

“…It has been demonstrated that the sympathetic activity of obese rats (4,24), renovascular hypertensive rats (5,25,26) and SHRs (6,27,28) is enhanced compared with normotensive rats. Hexamethonium is a ganglionic blocker (10,11) and reduces blood pressure in SHR and Wistar rats (8).…”