Intermedin in the Paraventricular Nucleus Attenuates Cardiac Sympathetic Afferent Reflex in Chronic Heart Failure Rats

Xian-Bing Gan,Ye-Bo Zhou,Hai-Jian Sun,Dan Chen,Ling-Li Zhang,Li-Yan Chen,Hong Zhou,Michael Bader

doi:10.1371/journal.pone.0094234

Abstract

Background and AimIntermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin. It has a wide distribution in the central nervous system (CNS) especially in hypothalamic paraventricular nucleus (PVN). Cardiac sympathetic afferent reflex (CSAR) is enhanced in chronic heart failure (CHF) rats. The aim of this study is to determine the effect of IMD in the PVN on CSAR and its related mechanisms in CHF rats.Methodology/Principal FindingsRats were subjected to left descending coronary artery ligation to induce CHF or sham-operation (Sham). Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Acute experiments were carried out 8 weeks after coronary ligation or sham surgery under anesthesia. IMD and angiotensin II (Ang II) levels in the PVN were up-regulated in CHF rats. Bilateral PVN microinjection of IMD caused greater decreases in CSAR and the baseline RSNA and MAP in CHF rats than those in Sham rats. The decrease of CSAR caused by IMD was prevented by pretreatment with AM receptor antagonist AM22-52, but not CGRP receptor antagonist CGRP8-37. Ang II in the PVN significantly enhanced CSAR and superoxide anions level, which was inhibited by PVN pretreatment with IMD or tempol (a superoxide anions scavenger) in Sham and CHF rats.ConclusionIMD in the PVN inhibits CSAR via AM receptor, and attenuates the effects of Ang II on CSAR and superoxide anions level in CHF rats. PVN superoxide anions involve in the effect of IMD on attenuating Ang II-induced CSAR response.

Highlights

Cardiac sympathetic afferent reflex (CSAR), a sympathoexcitatory reflex, can be induced by stimulation of cardiac sympathetic afferents with exogenous or endogenous chemicals from myocardium during myocardial ischemia [1,2]
paraventricular nucleus (PVN) superoxide anions involve in the effect of IMD on attenuating angiotensin II (Ang II)-induced CSAR response
Microinjection of IMD (30 pmol) into the anterior hypothalamic area, which is adjacent to the PVN, had no significant effects on the CSAR and the baseline Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in chronic heart failure (CHF) rats

Summary

Introduction

Cardiac sympathetic afferent reflex (CSAR), a sympathoexcitatory reflex, can be induced by stimulation of cardiac sympathetic afferents with exogenous or endogenous chemicals from myocardium during myocardial ischemia [1,2]. Chronic heart failure (CHF) is accompanied by the enhanced sympathetic nerve activity (SNA) [3,4,5], and the enhanced CSAR partially contributes to the sympathetic activation in CHF rats [5,6,7]. Intermedin (IMD) is widely distributed in peripheral organs and central nervous system (CNS) and belongs to calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin [10,11,12,13]. Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin. It has a wide distribution in the central nervous system (CNS) especially in hypothalamic paraventricular nucleus (PVN). The aim of this study is to determine the effect of IMD in the PVN on CSAR and its related mechanisms in CHF rats

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