이태경 순천향대학교의과대학신경과학교실, 순천향대학교부천병원신경과어지럼센터 Autonomic nervous system on cardiovascular control Tae-Kyeong, MD, PhD Dizziness Center, Department of Neurology, College of Medicine, Soonchunhyang University, Soonchunhyang University Bucheon Hospital, Bucheon, Korea The autonomic nervous system plays important role on the optimal responses of the cardiovascular system to the fluctuating internal and external environment. The integrated autonomic control through parasympathetic and sympathetic divisions timely intervenes in the vasomotor tone and cardiac function. Through modulating the release of certain peptide hormones, autonomic nervous system also influences on the systemic volume which takes part in maintaining peripheral resistance. The central autonomic network harmonizes the diverse inputs from throughout the body and transmits the efferent activity to the heart and peripheral resistance vessels. Baroreflex conducts a major role in maintaining cardiovascular homeostasis. Impairment or derangement of this reflex can result in serious threatens such as orthostatic intolerance and neurocardiogenic syncope. Understanding of autonomic regulation on cardiovascular system is essential in managing various neurological and medical diseases. Key Words: Autonomic nervous system, Cardiovascular, Baroreflex 서론 자율신경계는신체내, 외부환경의변화에대해심혈관계를끊임없이조절함으로써항상성 (homeostasis) 을유지하는데있어중요한역할을한다. 자율신경계는교감신경과부교감신경을통해심장과혈관을조절함으로써심혈관계의안정성을유지하는데, 뇌간을포함한중추자율신경망은신체의다양한곳으로부터오는구심신호를통합하여적절한혈압과맥박의반응을유도한다. 혈압과맥박의동요 (fluctuation) 를조절하는것은이러한자율신경반사와펩타이드호르몬 (peptide hormone) 분비를통한내분비적작용에의하여이루어지는데, 궁극적으로는뇌를포함한중요장기로가는혈류를유지하는것이목적 Tae-Kyeong Lee, M.D., PhD Department of Neurology, College of Medicine, Soonchunhyang University, Soonchunhyang University Bucheon Hospital, 170, Jomaru-ro, Wonmi-gu, Bucheon 14584, Korea Tel: +82-32-621-5220 Fax: +82-32-621-5018 E-mail: xorudoc@schmc.ac.kr 이다. 심혈관계의자율신경조절에가장중요한역할을담당하는것은압수용기반사 (baroreflex) 로서순간적인혈압의변화를감지하여혈압과맥박의조절을통해심혈관계를안정시키며, 혈액량의변동에대해서펩타이드호르몬을분비하는데에도관여한다. 압수용기반사의이상은기립불내증 (orthostatic intolerance), 신경심장성실신 (neurocardiogenic syncope) 과같은문제를야기할수있다. 자율신경계의심혈관계조절에대한이해는내과적, 신경과적질환을진료하는데있어필수적이다. 본고에서는자율신경성심혈관계조절에대한이해를돕기위해심장조절, 압수용기반사, 호흡과심혈관계의관계로나누어해부생리학적관점으로기술하였다. 본론 1. 심장에대한자율신경계조절심장은상부흉추의중간외측척수 (intermediolateral) 에서유래된교감신경과연수의미주신경핵인모호핵 (ambigus nucleus) 과배측미주신경운동핵 (dorsal motor nucleus of 2 대한신경과학회 2017 년도제 36 차추계학술대회 - 강의록 -
Figure 1. Anatomy of the autonomic nervous systemand its control of the heart. vagus) 으로부터유래된미주신경에의한부교감신경으로부터동시에긴장성신경지배를받고있다 (Fig. 1) 1 부교감신경지배는미주신경의긴경로를통해동심방결절 (sinoatrial node) 과방실결절 (atrioventricular node) 근처의작은신경절 (ganglion) 들에연결된다. 신경절이전섬유 (preganglionic fiber) 인미주신경이아세틸콜린을분비하면심장의작은부교감신경절의니코틴수용체 (nocotinic receptor) 에결합하여짧은신경절이후섬유 (postganglionic fiber) 를통해다시아세틸콜린을분비하게된다. 신경절이후섬유에서분비된아세틸콜린은동심방결절과방실결절에있는무스카린수용체 (muscarinic receptor) 에결합함으로써심장을느리게뛰도록하는음성심박동수변동 (negative chronotropy), 심장수축을약하게하는음성수축력 (negative inotropy), 전도를느리게하는음성전도영향 (negative dromotropy), 심근의확장을더디게하는음성확장률 (negative lusitropy) 로작용한다. 부교감신경계의일반적작용은휴식을취하거나에너지를충전하는역할을하므로인간에서휴식을취할때는미주신경긴장도가증가하여심박수가분당약 70회이하가된다. 한편, 교감신경은흉추의척수옆신경절 (paravertebral ganglion) 과연결된짧은신경절이전섬유를통해아세틸콜린을분비하고, 척수옆신경절의니코틴수용체에결합하여신경절이후섬유를자극하여동심방결절과방실결절에연접하고있는긴아드레날린원심섬유 (adrenergic efferent fiber) 를통해노르에피네프린 (norepinephrine) 을분비하게하여 이것이베타-아드레날린수용체 (β-adrenergic receptor) 에결합함으로써심박동수를빠르게 (positive chronotropic), 수축을강하게 (positive inotropy), 전도를빠르게 (positive dromotropy), 심근의확장을원활하게 (positive lusitropy) 하는역할을한다. 이같은작용을통해교감신경계는부교감신경계와는다르게심박수를분당약 20회까지올리게한다. 이와같이교감신경계와부교감신경계는서로반대의역할을하지만이들이동시에작용하는것이아니라내적, 또는외적자극에대한반응에따라한쪽이억제되면서다른한쪽이자극되는식으로작용한다. 즉, 휴식을취하고있을때는부교감신경이우세한데, 이는무스카린수용체억제제 (muscarinic receptor antagonist) 인아트로핀과베타-아드레날린수용체억제제인프로프라놀롤 (propranolol) 을이용한실험으로증명되었다. 휴식을취하고있을때인체에아트로핀 (0.04 mg/kg) 을투입하였더니, 부교감신경계가억제되어심박수는분당 110회까지증가되었고, 프로프라놀롤을투입하였더니약 50회까지만감소되었다. 또한, 두가지약물을동시에투입하게되면심박동이약 100회정도에서왔다갔다하므로약 100회정도의심박수가심장고유의박동수 (intrinsic heart rate) 이며, 휴식을취하고있을때는부교감신경계가더우세하여심장고유의박동수를조절하고있는것이라하였다. 2 흥분하거나운동을시작할경우부교감신경이억제되면서교감신경이활성화되는과정을거치며, 다시안정상태로갈때는반대로교감신경의활성이감소하고부교감신경의활성화되는과정을거친다. 3 우심방에있는동방결절은특별한심근세포 (cardiac myocytes) 로서자동적으로리듬을형성하여후하측심방사이막 (interatrial septum) 에위치한동방결절로신호를보내게되고동방결절에서좌우측심실사이막 (interventricular septum) 에서심첨부 (cardiac apex) 까지뻗어있는히스다발 (His bundle) 을통해심장전도근육세포섬유 (Purkinje fiber) 를흥분시킴으로써심장을수축하게한다. 이러한심장고유의전도시스템에대한자율신경의영향은주로동방결절에작용하게되는데, 부교감신경의활성화로동방결절에있는신경절에서아세틸콜린이분비되면동방결절의무스카린수용체에결합하여심장근육세포의탈분극 (depolarization) 을느리게하고동시에교감신경절후신경섬유에서노르에피내프린이분비되는것을억제한다. 4 2. 압수용기반사 (baroreflexes) 혈압또는혈액량의변화는압수용기에의해감지되어 대한신경과학회 2017 년도제 36 차추계학술대회 - 강의록 - 3
이태경 Figure 2. Location of barorecptors and neural pathways mediating baroreflex responses. Arterial baroreceptro afferents innervated carotid sinuses, arotic arch and the right carotid artery-right subclavian artery juncture. Cardiopulmonary baroreceptors innervated veno-atrial juncture, atria, ventricles, and pulmonary vasculature. The baroreflexes modulate parasympathetic nerve activity (parasna) and sympathetic nerve activity (SNA) to numerous organ systems and vasopressin (AVH) release. Adapted from reference 자율신경에의한심혈관계조절이시작된다. 압수용기반사에는두가지종류의압수용기반사가작용하는데경동맥동 (carotid sinus) 과대동맥궁 (aortic arch) 에있는동맥압수용체 (arterial baroreceptor) 에의한반사와폐심장압수용체 (cardiopulmonary baroreceptor) 에의한반사가그것이다 (Fig. 2) 1,5 대동맥궁과경동맥동에는혈압의변화에민감하게작용하는기계적수용체 (mechanoreceptor) 가있어동맥압이높으면활동이증가하고, 낮으면활동이감소하여음성되먹이기기전에의해신속하게혈압의변동에대처하도록한다. 한편, 심장, 대정맥 (vena cava), 폐혈관계에는폐심장압수용체가있어흉곽내혈류량의변화에따라작용하므로다른말로혈량수용체 (volume receptor) 또는저압력압수용체 (low-pressure baroreceptor) 라고도한다. 대동맥궁에있는압력수용체의신경세포체는추체신경절 (petrosal ganglion) 에존재하고미주신경의구심성분으로서고립로핵 (nucleus tractus solitaries, NTS) 으로신호를전달한다. 경동맥동을지배하는신경세포체는결절신경절 (nodose ganglion) 에있고설인신경의구심성분으로서고립로핵에전달된다. 고립로핵은심혈관계, 호흡계, 그리고다른내장성분으로부터오는구심성신호를받아서부교감신경계와교감신경계의긴장성활동에영향을미친다. 6 고립로핵은하부연수의미측복외측연수 Figure 3. major nuclei involved in baroreflex control. Increases in BP and baroreceptor activity activate excitatory neural projections from nucleus tractus solitaries (NTS) to preganglionic parasympathetic neurons in nucleus ambigus (NA) and dorsal motor nucleus of vagus (DMNX) resulting in increases in parasympathetic nerve activity and decreases in HR. activation of excitatory projections from NTSto caudal ventrolateral medulla (CVLM) causes subsequent inhibition of premotor sympathetic neurons in rostral ventrolateral medulla (RVLM) that project to preganglionic sympathetic neurons in the intermediolateral (IML) column of the thoracolumbar spinal cord. Increased baroreceptor activity also inhibits secretion of AVP from magnocelluar neurons in paraventricular nucleus (PVN) and supraoptic nucleus (SON) of hypothalamus. Adapted from reference (caudal ventrolateral medulla, CVLM), 모호핵, 배측미주운동핵, 시상등으로신호를보낸다. CVLM은문측복외측연수 (rostral ventrolateral medulla, RVLM) 를긴장성으로억제하고있다가혈압의변동에대해 RVLM이작용하도록하는데, RVLM은교감신경계에의한혈관조절의중심으로서흉추의중간외측핵 (intermediolateral column) 으로원심성교감신경신호 (sympathetic efferents) 를보내여기에서신경절이전섬유 (preganglionic fiber) 가흉추신경절을통해나온다 (Fig. 3) 5 심박동과심박출량은교감신경성신호에의해서는증가되고, 부교감신경성신호에대해서는감소되는긴장성지배 (tonic innervation) 를받고있다. 뇌간에서심장으로보내지는부교감신경의원심섬유는미주신경을따라나오고, 교감신경의원심섬유는 RVLM에서나오게된다. 경동맥동과대동맥궁에서전신혈압의감소가감지되어고립로핵으로전달되면부교감신경계와교 4 대한신경과학회 2017 년도제 36 차추계학술대회 - 강의록 -
Figure 4. Effector mechanisms mediating reflex reponses to increases in barorecptor acitivity. Increases in arterial BP and barorecptor activity increase parasympathetic acitivity (parasna), decrease sympathetic activity (SNA), and inhibit release of AVP leading to an array of cardiovascular, humoral and renal responses. Decreases in arterial BP evoke directionally opposite reflex responses. A-V node, atrio-ventricular node; Ang II, angiotensin II; H 2O, water. Adapted from reference. 감신경계로보내지는긴장성활동이감소하게되고, 평소긴장성흥분신호를보내던미주신경성부교감신경계에대해서는흥분성활동이감소하게되어부교감신경에의하여억제되고있던심장의동심방결절 (sinoatrial node) 을풀어서심박출량과맥박을증가시키는방향으로작용하게하고, 평소긴장성억제를하고있던 RVLM에대해서는탈억제 (disinhibitory) 효과를나타내게하여교감신경에의한골격근혈관의긴장도를증가시켜말초혈관의저항성이커지도록함으로써혈압을올린다. RVLM이탈억제되는기전은다음과같다. RVLM은평소미측복외측연수 (caudal ventrolateral medulla, CVLM) 에의해억제되고있는데, CVLM은고립로핵에의해긴장성흥분신호를받고있다. 고립로핵으로부터오는긴장성신호가감소하게되면 CVLM의긴장도가감소하면서 RVLM이탈억제되는것이다. 동맥압의증가에의해압수용기반사가유발되어심장, 혈관, 호르몬분비등에미치는영향을반응을도식적으로표현하면 Fig. 4와같다. 5 경동맥동과대동맥궁에있는기계적압수용체는압력에의해반응하지만혈압에대해직접적으로반응하기보다는혈관벽에있는수용기의기계적변성 (mechanical deformation) 에대해반응한다. 따라서, 노화, 동맥경화, 만성고혈압과같은상황에서는압수용기반사의민감도가 감소할수있다. 또한, 평균동맥압의급격한변동에대해서는반응성이증가하지만평균동맥압의지속적인증가상태에서는압수용기의반응성이감소한다. 또한, 혈압상승후에혈압이감소하게될때압수용체활동은흥분후감소현상 (post-excitatory depression, PED) 을보인다. 이러한지속적인혈압의변화에대한압수용기적응 (baroreceptor adaptation) 은혈압-압수용기반응의관계를재설정하여지속적인고혈압에대해서는혈압과맥박을떨어뜨리는반응을하지않게되지만압수용기의반응성은유지됨으로써순간적인혈압의변동에대해서는반응을하게한다. 이러한압수용기적응은중추자율신경계에대해조절되는것으로보인다. 7,8 한편, 정맥성수용체에의한압수용기반사는중심정맥압 (central venous pressure) 의감소에대하여작용하므로혈류량의감소가가장큰자극이다. 폐와심장에있는수용체가자극되면동맥성수용체와같은경로를통해심장의부교감성원심신경과사지동맥의교감신경성반응을일으킨다. 압수용기반사에서주된신경전달물질은노르에피네프린으로서순간순간변화하는혈압에대해소동맥의긴장도를조절한다. 9 이에반해지속적기립성스트레스에대해서는레닌-안지오텐신-알도스테론계가작용한다. 신장의사구체옆기구 (juxtaglomerular appratus) 에서관류의변화가감지되면레닌이분비되고, 차례로안지오텐신과알도스테론이분비되어소디움의농도를높이며체액량이증가한다. 그외에항이뇨호르몬의분비도체액량의저하와고농도에대해반응하여분비되는데, 전상인에서는그역할이미미하지만, 노인에서와심한기립저혈압환자에서는매우중요한역할을하며, 기립저혈압환자에서오전에는심하지만주간에증상이심하지않은것은항이뇨호르몬의작용이도움을주기때문이다. 레닌에의한혈압의조절기전은자율신경계이상에의해서는별로영향을받지않지만항이뇨호르몬은뇌의도파민과오피오이드수용체에작용하므로다발성신경계위축증 (MSA) 의경우항이뇨호르몬의작용에장애가있으나, 말초성자율신경병증에서는항이뇨호르몬의반응이정상적이다. 10 3. 호흡과심혈관계조절의관계 호흡은호흡과관련된근육들의시간적-공간적협동운동에의해이루어지는신체의산소교환작용이다. 호흡근은폐의팽창과수축, 흡기와호기를일으키는펌프근육 대한신경과학회 2017 년도제 36 차추계학술대회 - 강의록 - 5
이태경 ( 횡경막, 복근, 늑간근 ) 과상기도를열고닫는근육 ( 구강인두, 후두근등 ) 으로구성된다. 각호흡근은서로조화를이루며신호를보내는신경원들에의해작동되는데, 연수에모여있는호흡신경원들이그주된역할을하며, 이곳을호흡중추 (respiratory center) 라고한다. 호흡중추는각부위에서오는기계적, 화학적, 신호를통합하여자동호흡의리듬을만든다. 호흡중추의해부학적위치는연수의배내측 (dorsomedial) 과복외측 (ventrolateral) 에상하로길게형성되어있는망상체 (reticular formation) 부위이며, 이중고립핵의복외측과붙어있는부분을배측호흡군 (dorsal respiratory group, DRG) 이라하고, 연수의복외측에있는부분을복측호흡군 (ventral respiratory group, VRG) 이라고한다. 복측호흡군은다시세부위로나뉘는데, 맨위쪽은후안면핵 (retrofacial nucleus) 과연관된 Bötzinger complex, 중간은모호핵과연관된입쪽외측호흡군 (rostral ventral respiratory group, rvrg), 맨아래쪽은후모호핵 (retroambiguus nucleus) 과연관된꼬리쪽외측호흡군 (caudal ventral respiratory group, cvrg) 으로구성되어있다. 12 각각의호흡중추는각부위마다흡기및호기의기능이구분되어있고, 고유척수로 (propriospinal pathway) 에의해서로연결되어호흡의리듬을만들어구척수로 (bulbospinal pathway) 를통하여척수의호흡운동신경원으로신호를보낸다. 13 운동은신체의산소요구량을증가시키고, 호흡의변화에의해심장순환계가반응한다는것은운동및체위변동의초기에자율신경계에의한호흡근의조절이필요하다는것을의미한다. 신체의움직임은폐포호흡 (alveolar ventilation) 에는별로영향을미치지않으나, 호흡근육의기계적견인, 즉, 횡경막, 복부근육의움직임, 긴장도등에변화를초래하여호흡을저해할수있다. 사지동물에서두위거상 (nose-up tilt) 을시키거나사람이누워있던자세에서일어나게되면횡격막이복강쪽으로하강하게되고복부근육이이완되어정맥환류 (venous return) 를떨어뜨려서기립저혈압을더욱심화시킬수있다. 이때중력의작용에대하여원활한호흡이유지되기위해서는횡격막근육과복근의활동성이증가하여야된다. 14 자율신경계는교감신경계와부교감신경계모두호흡계와밀접한관계가있으며, 특히, 심혈관계와호흡기계는외부환경과신체조직간의산소이용이라는측면에서상호작용을통하여협조를하여야한다. 호흡의변화는심박출량과심박동수의변화를일으키는데, 흡기시에는증가하고호 Figure 5. Coupling of the respiratory and cardiovascular system in the brainstem. AMB: ambiguus nucleus, BOT: Bötzinger complex, RFN: retrofacial nucleus, CX: external cuneate nucleus, DRG: dorsal respiratory group, NTS: nucleus tractus solitarius, DX: dorsal motor nucleus of vagus, IML: intermediolatera column, IO: inferior olivary nucleus, Pre-BOT: pre-bötzinger complex, cvrg: caudal ventral respiratory group, RAMB: retroambiguus nucleus, rvrg: rostral ventral respiratory group, RVLM: cardiovascular area of rostral ventrolateral medulla. 기시에는감소한다. 이러한호흡에의한심박동수의변화를호흡동성부정맥 (respiratory sinus arrhythmia, RSA) 라고하는데, 15 이러한작용은모호핵에있는심장억제성전신경원 (preganglionic cardioinhibitory neuron) 과문측배외측연수에있는교감신경흥분성신경원 (sympathoexcitatory neuron) 의활동에의해이루어진다. 16 심장의교감신경활동은흡기말에증가하고심장의미주신경활동은호기초에증가한다. 17 문측복외측연수는주된호흡신경원인 Bötzinger complex 와복측호흡군과밀접하게위치하여심혈관계- 호흡기계의통합에있어주된장소로생각된다 (Fig. 5). 18 RAS는여러심혈관계질환에서없어지거나줄어들수있어심혈관계건강상태를반영하기도한다. 19 References 1.Sinoway LI. Drew RC. Autonomic control of the heart: In Premier on the Autonomic nervous system. 3rd ed. Elsevier 2012;177-180. 2. Katona PG, McLean M, Dighton DH, Guz A. Sympathetic and parasympathetic cardiac control in athletes and nonathletes at rest. J Appl Physiol 1982;52:1652-1657. 3. Arai Y, Saul JP, Albrecht P, et al. Modulation of cardiac autonomic activity during and immediately after exercise. The American journal of physiology 1989;256:H132-141. 6 대한신경과학회 2017 년도제 36 차추계학술대회 - 강의록 -
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