Effect of adrenomedullin on the activity of barosensitive neurons in the rostral ventrolateral medulla of rats

( views:90, downloads:0 )
FAN Ming-Xin()
LI Xia()
WANG Jin()
CAO Yin-Xiang()
SHEN Lin-Lin()
ZHU Da-Nian()
Journal Title:
Volume 58, Issue 03, 2006
Key Word:
adrenomedullin;receptor;nitric oxide;rostral ventrolateral medulla;iontophoresis;extracellular recording

Abstract: To investigate the eletrophysiological effect of rat adrenomedullin (rADM) on barosensitive neurons in the rostral ventrolateral medulla (rVLM) and its potential mechanisms, the extracellular recording and multi-barrel iontophoresis methods were used. Of the 29 barosensitive neurons in the rVLM, 20 neurons demonstrated excitatory response to iontophoretically applied rADM and increased the firing rate from (10.8 ± 2.7) spikes/s to (14.6 ± 3.6), (19.8 ± 4.7) and (31.9 ± 6.4) spikes/s (P<0.05, n=20) at the current of 30, 60and 90 nA, respectively. Application of human adrenomedullin (22-52) [hADM (22-52)], a specific antagonist of rADM receptor,distinctly attenuated the augmentation of firing rate induced by rADM-the firing rate was increased by 15.4% [(11.4 ± 2.5) spikes/s, P<0.05, n=10]. Another antagonist, human calcitonin gene-related peptide (8-37) [hCGRP (8-37)] had no significant effect on rADM-induced excitation. Other 23 barosensitive neurons were recorded to test the influence of nitric oxide synthase (NOS) inhibitors on the excitatory effect of rADM. In 10 neurons, 7-NiNa (neuronal NOS inhibitor) decreased the firing rate from (10.1 ± 3.5) spikes/s to (7.5 ± 2.5), (5.3 ± 2.1) and (3.1 ± 1.4) spikes/s (P<0.05, n=10) at the current of 10, 20 and 40 nA, respectively. The excitatory effect of rADM (60 nA, 30 s) during 7-NiNa application was nearly eliminated and the magnitude of firing rate was increased only by 17%of the basal level (6.2 ± 1.9) spikes/s (P<0.05, n=7). While aminoguanidine (AG, iNOS inhibitor) increased the firing rate at the resting level from (11.5 ± 5.1) spikes/s to (17.8 ± 5.6), (22.5 ± 6.3) and (29.1 ± 6.4) spikes/s (P<0.05, n=8) at the current of 10, 20 and 40 nA in 8 barosensitive neurons, respectively. When rADM (60 nA, 30 s) was delivered during AG iontophoresis period, the firing rate significantly increased by 60% of the basal level [(22.5 ± 6.3) spikes/s, n=5]. These results indicate that rADM activates the barosensitive neurons in the rVLM directly and acts as a cardiovascular regulator, and that this function might be mediated by its specific receptor. NO, mainly neuronal-NOS-originated might be involved in the excitatory effect of rADM in the rVLM.

  • [1]Hinson JP,Kapas S,Smith DM.Adrenomedullin,a multifunctional regulatory peptide.Endocr Rev 2000;21(2):138-167
  • [2]Owji AA,Smith DM,Coppock HA,Morgan DG,Bhogal R,Ghatei MA,Bloom SR.An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat.Endocrinol 1995;136(5):2127-2134
  • [3]Satoh F,Takahashi K,Murakami O,Totsune K,Sone M,Ohneda M,Abe K,Miura Y,Hayashi Y,Sasano H.Adrenomedullin in human brain,adrenal glands and tumor tissues of pheochromocytoma,ganglioneuroblastoma and neuroblastoma.J Clin Endocrinol Metab 1995;80(5):1750-1752
  • [4]Serrano J,Uttenthal LO,Martinez A,Fernandez AP,Martinez de Velasco J,Alonso D,Bentura ML,Santacana M,Gallardo JR,Martinez-Murillo R,Cuttitta F,Rodrigo J.Distribution of adrenomedullin-like immunoreactivity in the rat central nervous system by light and electron microscopy.Brain Res 2000;853:245-268
  • [5]Oliver KR,Kane SA,Salvatore CA,Mallee JJ,Kinsey AM,Koblan KS,Keyvan-Fouladi N,Heavens RP,Wainwright A,Jacobson M,Dickerson IM,Hill RG.Cloning,characterization and central nervous system distribution of receptor activity modifying proteins in the rat.Eur J Neurosci 2001;14(4):618-628
  • [6]Oliver KR,Wainwright A,Heavens RP,Hill RG,Sirinathsinghji DJ.Distribution of novel CGRP1 receptor and adrenomedullin receptor mRNAs in the rat central nervous system.Brain Res Mol Brain Res 1998;57(1):149-154
  • [7]Xu Y,Krukoff TL.Decrease in arterial pressure induced by adrenomedullin in the hypothalamic paraventricular nucleus is mediated by nitric oxide and GABA.Regul Pept 2004;119(1-2):21-30
  • [8]Smith PM,Ferguson AV.Adrenomedullin acts in the rat paraventricular nucleus to decrease blood pressure.J Neuroendocrinol 2001;13(5):467-471
  • [9]Allen MA,Smith PM,Ferguson AV.Adrenomedullin microinjection into the area postrema increases blood pressure.Am J Physiol 1997;272(6 Pt 2):R1698-R1703
  • [10]Ji SM,He RR.Microinjection of adrenomedullin into rostral ventrolateral medulla increases blood pressure,heart rate and renal sympathetic nerve activity in rats.Acta Physiol Sin (生理学报) 2002;54(6):460-466
  • [11]Xu Y,Krukoff TL.Adrenomedullin in the rostral ventrolateral medulla increases arterial pressure and heart rate:roles of glutamate and nitric oxide.Am J Physiol Regul Integr Comp Physio1 2004;287(4):R729-R734
  • [12]Chalmers J,Pilowsky P.Brainstem and bulbospinal neuro-transmitters systems in the control of blood pressure.J Hypertens 1991;9:675-694
  • [13]Dampney RA.The subretrofacial vasomotor nucleus:anatomical,chemical and pharmacological properties,and role in cardiovascular regulation.Prog Neurobiol 1994;42:197-227
  • [14]Dampney RA,Horiuchi J,Tagawa T,Fontes MA,Potts PD,Polson JW.Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone.Acta Physiol Scand 2003;177(3):209-218
  • [15]Martins-Pinge MC,Baraldi-Passy I,Lopes OU.Excitatory effects of nitric oxide within the rostral ventrolateral medulla of freely moving rats.Hypertension 1997;30(3Pt2):704-707
  • [16]Terui N,Saeki Y,Kumada M.Barosensory neurons in the ventrolateral medulla in rabbits and their responses to various afterent inputs from peripheral and central sources.J Physiol 1986;36:1141-1164
  • [17]Smith DM,Coppock HA,Withers DJ,Owji AA,Hay DL,Choksi TP,Chakravarty P,Legon S,Poyner DR.Adrenomedullin:receptor and signal transduction.Biochem Soc Trans 2002;30(4):432-437
  • [18]Flahaut M,Pfister C,Rossier BC,Firsov D.N-glycosylation and conserved cysteine residues in RAMP3 play a critical role for the functional expression of CRLR/RAMP3 adrenomedullin receptor.Biochem 2003;42(34):10333-10341
  • [19]Fischer JA,Muff R,Bom W.Functional relevance of G-proteincoupled-receptor-associated proteins,exemplified by receptoractivity-modifying proteins (RAMPs).Biochem Soc Trans 2002;30(4):455-460
  • [20]Muff R,Born W,Fischer JA.Adrenomedullin selectivity of calcitonin-like receptor/receptor activity modifying proteins.Hypertens Res 2003;26 Suppl:S3-S8
  • [21]Hay DL,Howitt SG,Conner AC,Schindler M,Smith DM,Poyner DR.CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors:a comparison of effects of adrenomedullin22-52,CGRP8-37 and BIBN4096BS.Br J Pharmacol 2003;140(3):477-486
  • [22]Xu Y,Krukoff TL.Adrenomedullin stimulates nitric oxide release from SK-N-SH Human neuroblastoma cells by modulating intracellular calcium mobilization.Endocrinology 2005;146 (5):2295-2305
  • [23]Chan JY,Chan SH,Chang AY.Differential contributions of NOS isoforms in the rostral ventrolateral medulla to cardiovascular responses associated with mevinphos intoxication in the rat.Neuropharmacology 2004;46(8):1184-1194
  • [24]Chang AY,Chan JY,Chan SH.Differential distribution of nitric oxide synthase isoforms in the rostral ventrolateral medulla of the rat.J Biomed Sci 2003;10 (3):285-291
  • [25]Ishide T,Maher TJ,Ally A.Role of nitric oxide in the ventrolateral medulla on cardiovascular responses and glutamate neurotransmission during mechanical and thermal stimuli.Pharmacol Res 2003;47(1):59-68
  • [26]Paxinos G,Watson C.The Rat Brain in Stererotaxic Coordinates.4th ed.San Diego:Academic Press,1999,64-69
  • [27]Beltowski J,Jamroz A.Adrenomedullin-what do we know 10 years since its discovery? Pol J Pharmacol 2004;56:5-27
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615 Email:yiyao@wanfangdata.com.cn