Cardiac sympathetic afferent reflex response to intermedin microinjection into paraventricular nucleus is mediated by nitric oxide and γ-amino butyric acid in hypertensive rats
Restricted accessResearch articleFirst published online October, 2014
Cardiac sympathetic afferent reflex response to intermedin microinjection into paraventricular nucleus is mediated by nitric oxide and γ-amino butyric acid in hypertensive rats
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 GABAA 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.
HongYHayDLQuirionRPoynerDR. The pharmacology of adrenomedullin 2/intermedin. Br J Pharmacol2012; 166: 110–20.
2.
RohJChangCLBhallaAKleinCHsuSY. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem2004; 279: 7264–74.
3.
TakahashiKKikuchiKMaruyamaYUrabeTNakajimaKSasanoHImaiYMurakamiOTotsuneK. Immunocytochemical localization of adrenomedullin 2/intermedin-like immunoreactivity in human hypothalamus, heart and kidney. Peptides2006; 27: 1383–9.
4.
TakahashiKMorimotoRHiroseTSatohFTotsuneK. Adrenomedullin 2/intermedin in the hypothalamo-pituitary-adrenal axis. J Mol Neurosci2011; 43: 182–92.
5.
TaylorMMBagleySLSamsonWK. Intermedin/adrenomedullin-2 acts within central nervous system to elevate blood pressure and inhibit food and water intake. Am J Physiol Regul Integr Comp Physiol2005; 288: R919–27.
6.
JollyLMarchJEKempPABennettTGardinerSM. Mechanisms involved in the regional haemodynamic effects of intermedin (adrenomedullin 2) compared with adrenomedullin in conscious rats. Br J Pharmacol2009; 157: 1502–13.
7.
RenYSYangJHZhangJPanCSYangJZhaoJPangYZTangCSQiYF. Intermedin 1-53 in central nervous system elevates arterial blood pressure in rats. Peptides2006; 27: 74–9.
8.
BiaggioniI. Should we target the sympathetic nervous system in the treatment of obesity-associated hypertension?Hypertension2008; 51: 168–71.
9.
HanYYuanNZhangSJGaoJShiZZhouYBGaoXYZhuGQ. c-Src in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats. Pflugers Arch2011; 461: 437–46.
10.
HogarthAJMackintoshAFMaryDA. The effect of gender on the sympathetic nerve hyperactivity of essential hypertension. J Hum Hypertens2007; 21: 239–45.
11.
LiPSunHJCuiBPZhouYBHanY. Angiotensin-(1-7) in the rostral ventrolateral medulla modulates enhanced cardiac sympathetic afferent reflex and sympathetic activation in renovascular hypertensive rats. Hypertension2013; 61: 820–7.
12.
RubingerDBackenrothRSapoznikovD. Sympathetic activation and baroreflex function during intradialytic hypertensive episodes. PLoS One2012; 7: e36943–e36943.
13.
ManciaGGrassiGGiannattasioCSeravalleG. Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension1999; 34: 724–8.
14.
MoriseTHoritaMKitagawaIShinzatoRHoshibaYMasuyaHSuzukiMTakekoshiN. The potent role of increased sympathetic tone in pathogenesis of essential hypertension with neurovascular compression. J Hum Hypertens2000; 14: 807–11.
15.
RahnKHBarenbrockMHausbergM. The sympathetic nervous system in the pathogenesis of hypertension. J Hypertens Suppl1999; 17: S11–4.
16.
Del ColleSMorelloFRabbiaFMilanANasoDPuglisiEMulateroPVeglioF. Antihypertensive drugs and the sympathetic nervous system. J Cardiovasc Pharmacol2007; 50: 487–96.
17.
FisherJPFadelPJ. Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension. Exp Physiol2010; 95: 572–80.
18.
GrassiGSeravalleGQuarti-TrevanoF. The ‘neuroadrenergic hypothesis’ in hypertension: current evidence. Exp Physiol2010; 95: 581–6.
19.
MallianiAMontanoN. Emerging excitatory role of cardiovascular sympathetic afferents in pathophysiological conditions. Hypertension2002; 39: 63–8.
20.
ZhuGQXuYZhouLMLiYHFanLMWangWGaoXYChenQ. Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats. Exp Physiol2009; 94: 785–94.
21.
YuanNZhangFZhangLLGaoJZhouYBHanYZhuGQ. SOD1 gene transfer into paraventricular nucleus attenuates hypertension and sympathetic activity in spontaneously hypertensive rats. Pflugers Arch2013; 465: 261–70.
22.
HanYSunHJLiPGaoQZhouYBZhangFGaoXYZhuGQ. Angiotensin-(1-7) in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats. PLoS One2012; 7: e48966–e48966.
23.
ZhongMKDuanYCChenADXuBGaoXYDeWZhuGQ. Paraventricular nucleus is involved in the central pathway of cardiac sympathetic afferent reflex in rats. Exp Physiol2008; 93: 746–53.
24.
HashimotoHKitamuraKKawasakiMSaitoTSuzukiHOtsuboHOhbuchiTYokoyamaTFujiharaHTakeiYUetaY. Adrenomedullin 2/intermedin-like immunoreactivity in the hypothalamus and brainstem of rats. Auton Neurosci2008; 139: 46–54.
25.
Chan SH, Chan JY. Brain stem NOS and ROS in neural mechanisms of hypertension. Antioxid Redox Signal. Epub ahead of print 2013.
26.
GamboaAOkamotoLEDiedrichAChoiLRobertsonDFarleyGParanjapeSBiaqqioniL. Sympathetic activation and nitric oxide function in early hypertension. Am J Physiol Heart Circ Physiol2012; 302: H1438–43.
27.
ShinoharaKHirookaYKishiTSunagawaK. Reduction of nitric oxide-mediated γ-amino butyric acid release in rostral ventrolateral medulla is involved in superoxide-induced sympathoexcitation of hypertensive rats. Circ J2012; 76: 2814–21.
28.
YangJHPanCSJiaYXZhangJZhaoJPangYZYangCSQiYF. Intermedin1–53 activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Biochem Biophys Res Commun2006; 341: 567–72.
29.
KandilciHBGumuselBLipptonH. Intermedin/adrenomedullin-2 (IMD/AM2) relaxes rat main pulmonary arterial rings via cGMP-dependent pathway: role of nitric oxide and large conductance calcium-activated potassium channels (BK(Ca)). Peptides2008; 29: 1321–28.
30.
NorthcottCABilleckeSCraigTHinojosa-LabordeCPatelKPChenAFD'AlecyLGHaywoodJR. Nitric oxide synthase, ADMA, SDMA, and nitric oxide activity in the paraventricular nucleus throughout the etiology of renal wrap hypertension. Am J Physiol Heart Circ Physiol2012; 302: H2276–84.
31.
ChenQHHaywoodJRToneyGM. Sympathoexcitation by pvn-injected bicuculline requires activation of excitatory amino acid receptors. Hypertension2003; 42: 725–31.
32.
MartinDSSeguraTHaywoodJR. Cardiovascular responses to bicuculline in the paraventricular nucleus of the rat. Hypertension1991; 18: 48–55.
33.
ZhongMKShiZZhouLMGaoJLiaoZHWangWGaoXYZhuGQ. Regulation of cardiac sympathetic afferent reflex by GABA(A) and GABA(B) receptors in paraventricular nucleus in rats. Eur J Neurosci2008; 27: 3226–32.
34.
XuYKrukoffTL. Decrease in arterial pressure induced by adrenomedullin in the hypothalamic paraventricular nucleus is mediated by nitric oxide and GABA. Regul Pept2004; 119: 21–30.
35.
ChenADZhangSJYuanNXuYDeWGaoXYZhuGQ. AT1 receptors in paraventricular nucleus contribute to sympathetic activation and enhanced cardiac sympathetic afferent reflex in renovascular hypertensive rats. Exp Physiol2011; 96: 94–103.
36.
ZhangLXiongXQFanZDGanXBGaoXYZhuGQ. Involvement of enhanced cardiac sympathetic afferent reflex in sympathetic activation in early stage of diabetes. J Appl Physiol2012; 113: 47–55.
37.
ZhuGQGaoXYZhangFWangW. Reduced nitric oxide in the rostral ventrolateral medulla enhances cardiac sympathetic afferent reflex in rats with chronic heart failure. Sheng Li Xue Bao2004; 56: 47–53.
38.
ZhouYBSunHJChenDLiuTYHanYWangJJTangCSKangYMZhuGQ. Intermedin in paraventricular nucleus attenuates sympathetic activity and blood pressure via nitric oxide in hypertensive rats. Hypertension2014; 63: 330–7.
39.
Lin ChangCRohJParkJIKleinCCushmanNHaberbergerRVHsuSY. Intermedin functions as a pituitary paracrine factor regulating prolactin release. Mol Endocrinol2005; 19: 2824–38.
40.
TaylorMMSamsonWK. Stress hormone secretion is altered by central administration of intermedin/adrenomedullin-2. Brain Res2005; 1045: 199–205.
41.
Cam-EtozBIsbil-BuyukcoskunNOzlukK. Cardiovascular effects of the intracerebroventricular injection of adrenomedullin: roles of the peripheral vasopressin and central cholinergic systems. Braz J Med Biol Res2012; 45: 250–5.
42.
BellDMcDermottBJ. Intermedin (adrenomedullin-2): a novel counter-regulatory peptide in the cardiovascular and renal systems. Br J Pharmacol2008; 153(Suppl 1): S247–62.
43.
YenDHChenLCShenYCChiuYCHoICLouYJChenICYenJC. Protein kinase A-dependent neuronal nitric oxide synthase activation mediates the enhancement of baroreflex response by adrenomedullin in the nucleus tractus solitarii of rats. J Biomed Sci2011; 18: 32–32.
44.
LiPSunHJHanYWangJJZhangFTangCSZhouYB. Intermedin enhances sympathetic outflow via receptor-mediated cAMP/PKA signaling pathway in nucleus tractus solitarii of rats. Peptides2013; 47: 1–6.
45.
LiYFWangWMayhanWGPatelKP. Angiotensin-mediated increase in enal sympathetic nerve discharge within the PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol2006; 290: R1035–43.
46.
FollwellMJFergusonAV. Adrenomedullin influences magnocellular and parvocellular neurons of paraventricular nucleus via separate mechanisms. Am J Physiol Regul Integr Comp Physiol2002; 283: R1293–302.
47.
HsuYCChenHIKuoYMYuLHuangTYChenSJChuangJIWuFSJenCJ. Chronic treadmill running in normotensive rats resets the resting blood pressure to lower levels by upregulating the hypothalamic GABAergic system. J Hypertens2011; 29: 2339–48.
48.
LiDPChenSRPanHL. Nitric oxide inhibits spinally projecting paraventricular neurons through potentiation of presynaptic GABA release. J Neurophysiol2002; 88: 2664–74.
49.
ZhangKPatelKP. Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA. Am J Physiol1998; 275: R728–34.
