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1 대한내과학회지 : 제 86 권제 6 호 종설 (Review) 바소프레신제 2 수용체길항제의임상적용 한양대학교의과대학내과학교실 오일환 김근호 Clinical Application of V2 Receptor Antagonists Il Hwan Oh and Gheun-Ho Kim Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea Hyponatremia results from a relative excess of total body water compared with the sodium content. Except for primary polydipsia, vasopressin activation plays a major role in pathogenesis of water retention. Consequently, the increase of solute-free water clearance by inactivating vasopressin action would be a more reasonable therapeutic approach than the addition of sodium. The V2 vasopressin receptor is mainly localized to the collecting ducts in the kidney and causes water reabsorption via water channels. Selective V2 receptor antagonists or vaptans were recently introduced to clinical practices and may be useful for correcting dilutional hyponatremia. Clinical trials have shown that vaptans are effective in increasing the serum sodium concentration in patients with syndrome of inappropriate anti-diuresis and congestive heart failure and that they might be safe as long as patients are allowed free accesses to water. However, the indications for using vaptans need to be more refined, and the question of their long-term cost-effectiveness should be answered. In addition, the potential roles of vaptans in ameliorating the growth of cysts in polycystic kidney disease, saving diuretics in edematous disorders, and retarding the progression of chronic kidney disease are being explored. (Korean J Med 2013;85: ) Keywords: Complication; Critically-ill; Prevention; ICU 체내수분평형은섭취와배설이균형을이루어유지되는데, 만약요배설 ( 희석 ) 능을초과할정도로수분섭취가지나치든지혹은섭취한수분만큼충분히요배설 ( 희석 ) 이이루어지지않으면비정상적수분축적이발생한다. 수분축적은오스몰농도의감소를초래하는데, 세포외액에서가장많은용질이나트륨이므로그농도가감소하는저나트륨혈증으로발현한다. 따라서저나트륨혈증을치료하기위해서는비정상적인수분축적을교정하는접근방법이병태생리에부합 한다고할것이다. 이제까지저나트륨혈증을교정하는여러방법들이사용되어왔으나효과와부작용등, 병태생리학적으로적합하지못한부분들이있었다. 이에비하여최근임상에도입되어처방되고있는바소프레신제2수용체길항제 (V2 receptor antagonists, vaptans) 는선택적으로수분을배설시키는장점을가지고있다. 이글에서는바소프레신2수용체길항제의임상적용에대해최신지견을요약하고자한다. Correspondence to Gheun-Ho Kim, M.D., Ph.D. Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Seungdong-gu, Seoul , Korea Tel: , Fax: , kimgh@hanyang.ac.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Il Hwan Oh, et al. Vasopressin receptor antagonists - 저나트륨혈증병인에서바소프레신의역할 나트륨농도는나트륨의양 (content) 과총체수분 (total body water) 의비로구할수있으므로 [1] 나트륨량이감소하거나총체수분이증가할때나트륨농도가감소한다. 실제이러한결과를초래하는저나트륨혈증의병인을나트륨 ( 체액 ) 결핍에의해이차적으로수분이축적되는경우와나트륨결핍을동반하지않고일차적으로수분이축적되는경우로대별할수있다 (Table 1). 일차성수분축적은일차성다음증처럼수분섭취가지나치거나부적절항이뇨증후군 (syndrome of inappropriate anti-diuresis) 과같이요희석능장애가있을때발생한다. 이차성수분축적의원인은구토, 이뇨제복용등절대적체액결핍과울혈성심부전, 간경화, 신증후군등유효순환체액량결핍의경우로구분할수있다. 후자는이차적으로나트륨축적에따른부종을동반하는특징이있다. 이러한저나트륨혈증의주요원인가운데일차성다음증을제외한나머지경우에모두바소프레신활성화가중요하 Table 1. Pathogenesis of hyponatremia Causes Prototypes Primary water retention Excessive water intake Primary polydipsia Impaired urinary dilution SIAD Secondary water retention (primary sodium deficit) Absolute hypovolemia Sodium loss Effective arterial blood volume deficiency CHF, LC, NS SIAD, Syndrome of inappropriate anti-diuresis; CHF, congestive heart failure; LC, liver cirrhosis; NS, nephrotic syndrome. 게작용한다. 부적절항이뇨증후군에서는체액의오스몰농도가감소했음에도불구하고바소프레신분비가부적절하게증가하여저나트륨혈증이초래된것이지만울혈성심부전, 간경화및신증후군에서저나트륨혈증을초래한바소프레신분비의항진은유효순환체액량감소에따른적절한생리학적반응이라고할수있다. 어느경우든항진된바소프레신작용을신장의바소프레신제2수용체수준에서차단한다면수분배설을촉진시켜저나트륨혈증을호전시킬수있을것이다. 바소프레신은시상하부에서생성된후뇌하수체후엽에저장되었다가오스몰농도상승혹은체액결핍에의해그분비가자극되어체내곳곳에분포한바소프레신수용체와결합함으로써작용을발휘한다 (Table 2). 이제까지알려진바소프레신수용체는세가지가있는데, 신장에서수분재흡수에작용하는바소프레신수용체가 V2 수용체이고, V1 혹은 V1a 수용체는주로혈관수축, V3 혹은 V1b 수용체는뇌하수체에서 ACTH 분비에작용한다고알려졌다 [2]. 바소프레신제2수용체는집합관과비후상행각기저외측막에분포하여각각 AQP2 수분통로와 NKCC2 나트륨운반체를활성화시킴으로써요농축에기여한다 [3]. 바소프레신제2수용체길항제및그작용표 1에제시된저나트륨혈증의주요원인네가지가운데과도한수분섭취와나트륨소실의경우는각각수분섭취제한과나트륨보충을통해비교적쉽게교정할수있다. 이에비해부적절항이뇨증후군과부종질환에서는기저요인 Table 2. Vasopressin receptor location and functions Receptor Localization Functions V1a Vascular smooth muscle Vasoconstriction, myocardial hypertrophy Platelets Platelet aggregation Hepatocytes Glycogenolysis, urea synthesis Myometrium Uterine contraction V1b (or V3) Anterior pituitary ACTH release V2 Kidney tubule Urinary concentration Vascular endothelium vwf and factor VIII release Vascular smooth muscle Vasodilation ACTH, adrenocorticotropin hormone; vwf, von Willebrand factor. Adapted by permission from Macmillan Publishers Ltd: Kidney Int (Reference 2)

3 - 대한내과학회지 : 제 86 권제 6 호통권제 646 호 Table 3. Conventional treatment for hypotonic euvolemic or hypervolemic hyponatremia Therapy Application Limitations Isotonic saline solution Hypovolemic hyponatremia Ineffective in dilutional hyponatremia Hypertonic saline Hyponatremia with serious signs and symptoms Possible overly rapid correction Fluid restriction Dilutional hyponatremia Modest efficacy, but poor compliance Loop diuretics Dilutional hyponatremia, especially hypervolemic hyponatremia Electrolyte imbalance Demeclocycline Dilutional hyponatremia Slow onset of action, nephrotoxicity Urea Euvolemic hyponatremia Unpleasant taste, limited experience Increased solute intake Hyponatremia secondary to decreased solute intake Unpleasant taste, limited experience Adapted from Reference 9, Am J Kidney Dis 62:366, Lehrich RW, Ortiz-Melo DI, Patel MB, Greenberg A, Role of vaptans in the management of hyponatremia, 2013, with permission from Elsevier. 에곧바로접근하기어려우므로저나트륨혈증을교정하기위한다양한방법들이시도되었다 (Table 3). 수분섭취제한이손쉽게적용할수있는첫째수단이지만그효과가크지않고환자들이따르기어렵다 [4]. 한편고장 (hypertonic) 식염수를주입하면혈청나트륨농도를효과적으로상승시킬수있다. 그러나저나트륨혈증이너무갑작스럽게교정되면삼투탈수초증후군 (osmotic demyelination syndrome) 과같은합병증이발생할우려가있고 [5,6] 장기간주입하면세포용적위축에따른세포대사의악영향을염려해야할것이다 [7]. 따라서나트륨농도계산식에서분자에해당하는나트륨을더하여나트륨농도를개선시키는방식보다분모인수분을줄여서저나트륨혈증을교정하는방법이병태생리에더부합하고부작용이적어서적절한방법이될수있다. 이러한접근방법으로서바소프레신제2수용체길항제를사용하여신장에서수분재흡수를차단하는치료기전을생각해볼수있다. 사구체에서여과된수분은근위세관과헨레고리관하행각을따라재흡수된후, 헨레고리관비후상행각과원위곡세관에서는수분이동이없다가마지막집합관부위에이르러바소프레신작용으로재흡수되면서최종요를배설시킨다. 혈중바소프레신이집합관주세포의기저외측막에분포한바소프레신제2수용체와결합하면 Gα 단백을자극하여 camp 생성을증가시키고이로부터 protein kinase A가활성화되어세포안에머물러있던 AQP2 수분통로를내강막으로이동시킨다 [8]. 그결과집합관의수분투과성이증가하는데바소프레신제2수용체길항제는이러한일련의과정을차단하는효과가있다 (Fig. 1) [9]. 또한바소프레신의장기자극은 AQP2 수분통로단백합성을증가시키므로, 바소프레신제2수용체길항제투여에의해 AQP2 수 Figure 1. Arginine vasopressin-induced change in water permeability in the collecting duct. VR2, vasopressin 2 receptor; camp, cyclic 3',5'-adenosine monophosphate; PKA, protein kinase A; AQP-2, aquaporin 2; AQP-3, aquaporin 3; AQP-4, aquaporin 4. Adapted from Reference 9, Am J Kidney Dis, 62:368, Lehrich RW, Ortiz-Melo DI, Patel MB, Greenberg A, Role of vaptans in the management of hyponatremia, 2013, with permission from Elsevier. 분통로단백합성을억제시켜집합관에서수분재흡수를억제하는효과를발휘하게될것이다 [10]. 1981년에최초로보고된펩티드바소프레신수용체길항제는반감기가짧고생체이용률이낮아서주사투여만가능했는데, 동물실험결과오히려바소프레신효과를증진시키는작용제역할을하였다 [11]. 이후개발된비펩티드 (nonpeptide) 바소프레신수용체길항제는생체이용률이높고반

4 - 오일환외 1 인. 바소프레신제 2 수용체길항제의임상적용 - Figure 2. Effects of the oral administration of OPC or furosemide alone on serum parameters in conscious male rats. Values are expressed as the means ± SE of six animals per group. Differences between each OPC or furosemide group and the control group were analyzed using one-way analysis of variance (ANOVA), followed by the two-tailed Dunnett s multiple-comparison test. * p < 0.05, ** p < 0.01, versus the control. Adapted with permission from Reference 15 Hirano T, Yamamura Y, Nakamura S, Onogawa T, Mori T. Effects of the V2-receptor antagonist OPC and the loop diuretic furosemide alone and in combination in rats. J Pharmacol Exp Ther 2000;292: Table 4. The characteristics of nonpeptide vasopressin receptor antagonists Compound Receptor (s) Route Manufacturer Conivaptan V1a and V2R IV a or Oral Astellas Lixivaptan V2R Oral CardioKine Tolvaptan V2R Oral a Otsuka Stavaptan V2R Oral Sanofi-Aventis VR, vasopressin receptor. FDA approval. Adapted by permission from Macmillan Publishers Ltd: Kidney Int (Reference 2) 감기가길어서경구투여가가능해졌다 [12]. 정상인에게 mozavaptan (OPC-31260) 을투여하면요량이용량- 의존적으로증가하는데그에반비례하여요삼투질농도가감소하므로이뇨효과는수분청소율 (solute-free water clearance) 증가로설명된다. 또한요량변화와관계없이요중나트륨배설은거의일정해서수분배설촉진제 (aquaretic) 로서특징을나타내었다 [13]. 이는종래의이뇨제가나트륨재흡수를차단하여그효과를발휘하는나트륨배설촉진제 (natriuretic) 로서작용하는것과대비된다. 즉, 바소프레신제2수용체길항제는수분이뇨를유발하고종래의이뇨제 ( 나트륨배설촉진제 ) 는삼투이뇨를유도하므로요량을증가시키는기전이서로다르다. 이러한차이는혈역학변화와신기능부작용에서로다른영향을미칠수있다. 이뇨제에따른나트륨소실이유효순환체액량결핍을초래하면심박동수증가, 혈압저하, 부정맥, 사구체여과율저하 ( 콩팥전질소혈증 ) 등이발생할수있으나, 전임상연구결과수분배설촉진제인바소프레신제2수용체길항제는이러한부작용을피할수있었다 [14]. 실험쥐에서 tolvaptan과 furosemide 의효과를비교했을때혈청나트륨농도증가효과가 tolvaptan에서더우수하였고고용량투여에서도 furosemide 와달리혈중요소질소및혈청크레아티닌상승이없었다. 두가지약물에서모두혈청바소프레신농도가상승했으나 tolvaptan의경우고용량 furosemide 에서나타난레닌활성도및알도스테론농도증가소견을동반하

5 - The Korean Journal of Medicine: Vol. 86, No. 6, 지않았다 (Fig. 2) [15]. 울혈성심부전환자에서비교한자료에서도 tolvaptan과 furosemide 가유사한이뇨효과를나타내었으나 furosemide 투여군에서요중나트륨및칼륨배설이증가하고신장혈류가감소한반면, tolvaptan 투여군에서는위약대조군에비해차이가없었다 [16]. 현재상용화되어전세계적으로사용할수있는비펩티드바소프레신수용체길항제에는 conivaptan, lixivaptan, tolvaptan, satavaptan 등네가지가있다 (Table 4). 최근국내에는 tolvaptan이도입되었고같은제약회사에서 tolvaptan에앞서개발한 mozavaptan은현재일본에서만발매되고있다 [17]. Conivaptan은경구및주사제제가있으나주사제제만처음으로미국 FDA 승인을받았고 V1a와 V2 수용체에모두작용하는특징이있다. V2 수용체에선택적으로작용하는경구제제중 tolvaptan이유일하게미국 FDA 승인을 2009년에받았다. 바소프레신제2수용체길항제의임상시험성적 Tolvaptan Tolvaptan (OPC-41061) 은과거에소개된 mozavaptan (OPC ) 에비해사람의 V2 수용체선택성을더욱강화시킨약제이다 [18]. 부적절항이뇨증후군과같은정상체액량 (euvolemic) 저나트륨혈증및울혈성심부전혹은간경화와같은과체액량 (hypervolemic) 저나트륨혈증환자에서활발한임상연구가진행되었다. 그중울혈성심부전환자를대상으로시행된대표적인연구가 EVEREST 임상시험이다 [19,20]. 보존적치료와병행하여 tolvaptan의효과를위약대조군과비교했을때초기에체중증가가개선되고저나트륨혈증이호전되는효과가우수하였다 [19]. 또한호흡곤란, 부종등심부전증상과경정맥팽창, 수포음등진찰소견이초기에대조군에비해 tolvaptan 투여군에서유의하게호전되었다 [20]. 그러나 2년에걸쳐장기간추적하였을때사망률과입원기간에있어서유의한차이를나타내지못하였다 [19]. 한편, EVEREST 연구대상자중혈청나트륨농도 130 mmol/l 미만의저나트륨혈증환자들을사후분석한결과에서는심혈관계사망또는입원이 tolvaptan 투여군에서유의하게낮았다 [21]. 입원초기에급성심부전이개선되는이유를 tolvaptan 투여후폐모세혈관쐐기압 (pulmonary capillary wedge pressure) 과우심방압이감소 하는혈역학적변화로설명할수있다 [22]. SALT와 SALTWATER 임상시험은 tolvaptan이 FDA 승인을얻도록결정적근거를제공하였다. SALT 연구에서는정상체액량혹은과체액량저나트륨혈증환자에서 tolvaptan을 30일간투여하면서 4일및 30일째혈청나트륨농도를조사하였다 [23]. 미국과미국이외의지역으로구분하여 SALT-1 및 SALT-2 연구가나란히진행되었고대조군과치료군에각각 100여명씩포함되었다. 최초용량 1일 15 mg으로시작하여반응에따라 30 mg 혹은 60 mg까지증량하였다. 그결과 4일째뿐아니라투여기간 1개월내내대조군에비해 tolvaptan 치료군에서혈청나트륨농도가유의하게개선되었다. Tolvaptan 투여후대개 5 내지 10일사이에저나트륨혈증이교정되었고그이후혈청나트륨농도가잘유지되다가투여를종료하면서서히대조군수준으로떨어졌다. Tolvaptan 투여후첫 3일에걸쳐혈청나트륨농도상승속도가빨랐으나그속도가 12 mmol/l를초과한예는전체 223명중 4명에불과했고그중임상문제로발현한예는없었다. 부적절항이뇨증후군환자를따로떼어분석한결과에서도유사한소견이었다 [24]. SALTWATER 연구는 SALT 연구의연장으로서장기간안정성과유효성을검증하고자시행되었다 [25]. SALT 연구에참여하였던대조군 55명과치료군 56명에게모두 tolvaptan 을복용시키면서약 2년간추적관찰하였다. 과거 tolvaptan 복용여부에관계없이모두 tolvaptan에의한효과를나타내었고, 대개 2주내에혈청나트륨농도가정상화되었다. 그러나간경화환자에서는울혈성심부전및부적절항이뇨증후군환자에비해저나트륨혈증개선효과가조금미흡하였다. 장기간추적중 10% 가까운환자에서빈뇨와구갈부작용을호소하였으나심각한부작용은보고되지않았다 [25]. 최근 tolvaptan의저나트륨혈증치료제로서역할외에상염색체우성다낭신질환에서효과가알려졌다. 이는다낭신에서낭종의성장이 camp 자극에기인하므로이를억제하면낭종의성장을줄이고나아가서신부전의진행을지연시킬수있으리라는실험연구에서비롯되었다 [26-28]. 고용량 ( 평균 95 mg/day) 의 tolvaptan을상염색체우성다낭신질환환자에서 3년간복용시킨결과위약군에비해전체신장용적의증가와신기능감소속도를둔화시키는효과가있었다 [29]. 그러나치료군에서구갈, 빈뇨, 다뇨등요증상외에간기능이상소견으로중도탈락률이높은문제가발견되어

6 - Il Hwan Oh, et al. Vasopressin receptor antagonists - 결국 FDA에서간손상의위험을경고하기에이르렀다 [30]. Conivaptan 정상체액량또는과체액량저나트륨혈증환자를대상으로 conivaptan (YM087) 효과에대한여러임상연구가수행되었다. 경구 conivaptan 40 혹은 80 mg을매일 5일간투여하였을때혈청나트륨농도가효과적으로개선되었고 [31,32], 주사제 conivaptan을 40 혹은 80 mg/day 속도로 4일에걸쳐경정맥주입하였을때역시대조군에비해저나트륨혈증교정효과가우수하였다 [33,34]. 다만주사투여의경우일부환자에서주사부위에부작용이관찰되었다. V2 수용체뿐아니라 V1a 수용체를차단하는 conivaptan의독특한약리작용은울혈성심부전환자에서치료효과를더기대하도록한다 [35]. 그러나실제로심부전환자에서선택성 V2 수용체길항제에비해더뚜렷한치료효과가있는지아직분명하지않다. 급성심부전환자를대상으로시행한예비연구에서경정맥 conivaptan 투여로요량을증가시켰다는보고가있다 [36]. 한편, 간경화환자에서 V1a 수용체가차단되면내장혈관확장에따른문맥압상승과함께정맥류출혈의가능성이염려된다 [37]. Lixivaptan Lixivaptan (VPA-985) 은초기에주로간경화환자들을대상으로연구가시행되어저나트륨혈증개선효과를보고하였다 [38,39]. 울혈성심부전환자에서도다양한용량이시도되어유의한요량증가가관찰되었다 [40]. 부적절항이뇨증후군과같은정상체액량저나트륨혈증환자에서도 lixivaptan을 1일 25 내지 100 mg 경구투여하고 7일째 [41] 및 30일째 [42] 혈청나트륨농도가유의하게상승하였다. Satavaptan Satavaptan (SR121463B) 역시부적절항이뇨증후군환자에서저나트륨혈증개선효과를보고하였다 [43]. 하루에 25 혹은 50 mg을 5일내지 12개월간경구투여하였을때정상체액량저나트륨혈증을단기혹은장기적으로교정시킬수있는가능성을제시하였다. 이후보고된연구들은주로간경화환자들을대상으로시행되었다. 경구 satavaptan을 1일 5 내지 25 mg 용량으로 14일간투여하였을때저나트륨혈증과함께복수가호전되었다 [44]. 간경화환자에서저나트륨혈증 여부와무관하게복수의재발을줄이고 [45] 이뇨제효과를증진시킨다고 [46] 보고된바있으나최근시행된대규모장기간대조연구에서복수조절의효과를증명하는데실패하였다 [47]. 바소프레신제2수용체길항제의적응증이상의임상시험성적들을종합할때, 바소프레신제2수용체길항제의가장분명한적응증은부적절항이뇨증후군으로대표되는정상체액량저나트륨혈증이다. 그러나약물과같은기저요인을찾아제거하면서수분제한을먼저시도하는노력이필요하다. 만약고염고단백식이와함께소량의루프이뇨제에도반응하지않는다면바소프레신제2수용체길항제투여가유용하다. 과체액량저나트륨혈증중에서바소프레신제2수용체길항제효과가가장기대되는경우가울혈성심부전이다. 고식적방법인이뇨제, 레닌-안지오텐신계차단제등에반응없다면바소프레신제2수용체길항제를추가하여저나트륨혈증개선과함께심부전증상의호전을기대할수있다. 한편, 과거에기대를모았던복수동반간경화환자의경우는장기효과가분명하지못할뿐아니라간기능이상부작용을염려해야하므로처방이곤란하다. 만약환자의체액량이부족해보이는저나트륨혈증환자라면반드시등장식염수주입을우선시도한다. 증상을동반한급성저나트륨혈증에서도바소프레신제2수용체길항제는권고되지않는다. 대신고장식염수주입과같이혈청나트륨증가속도를예측할수있는고식적방법을사용한다. 요컨대증상이심하지않은만성저나트륨혈증환자에서고식적인치료방법으로혈청나트륨농도가교정되지않을때바소프레신제2수용체길항제를처방한다. Tolvaptan의경우최초 15 mg을아침에투여하여 8시간지나서혈청나트륨농도가적절한속도가상승하는지추적하고그반응에따라다음날투여용량을결정한다. 환자의구갈에따라수분섭취가부족하지않도록주의할필요가있다. 향후전망저나트륨혈증은질환자체가아니라다양한원인에의한증후군으로서결과적인현상이라고할수있다. 따라서바소

7 - 대한내과학회지 : 제 86 권제 6 호통권제 646 호 프레신제2수용체길항제가저나트륨혈증을교정하는데있어서병태생리학적으로유용하지만과연근본적인치료수단으로써환자의사망률개선까지기대할수있는지는의문스럽다. 이에따라우리나라건강보험급여와 FDA에서는저나트륨혈증치료를위한 tolvaptan 사용을 30일이내로제한하였다. 여기에는비싼가격의바소프레신제2수용체길항제비용부담이고려되었을것이다. 한편, SALT 와 EVEREST 연구결과를분석한약물경제성평가에서는 tolvaptan의입원기간단축효과가더유리하였다고주장한다 [48,49]. 또한증상이뚜렷하지않더라도만성저나트륨혈증을교정하지않으면보행장애에따른낙상과골절이증가할위험이있다 [50,51]. 따라서과연어떠한원인의얼마나심한저나트륨혈증을고가의바소프레신제2수용체길항제로서얼마동안어느정도까지개선시키는것이바람직한지해답이필요하다. 최초바소프레신제2수용체길항제가수분을선택적으로배설시키는역할에초점맞추어졌지만신장내 V2 수용체분포와바소프레신작용을고려할때나트륨배설에미치는효과도상상할수있다 [52]. 즉, 비후상행각의 V2 수용체를차단시키고집합관의상피나트륨통로 (ENaC) 발현억제에따른요나트륨배설증가를기대할수있다 [10]. 이러한작용은울혈성심부전환자에서기존이뇨제효과를상승시키는데기여할것이다. 최근루프이뇨제에반응하지않는신증후군환자에서도그유용성이보고되었으므로 [53] 향후불응성부종치료제로서적용해볼만하다. 상염색체우성다낭신질환에서 tolvaptan 효과가기대되고있으나아직판단하기어렵다. 고용량장기간투여에따른부작용여부와경제적부담이또한해결해야할과제이다. 한편, 아직실험적수준에머물러있으나만성콩팥병진행에있어서바소프레신의역할이최근주목받고있으므로 [54,55], 바소프레신수용체길항제의저나트륨혈증치료외에다양한신장질환치료수단으로서의역할을기대해본다. 이해충돌사항본논문의교신저자는한국오츠카제약의자문과심포지엄강사로참여한바있음. 중심단어 : 저나트륨혈증 ; 부적절항이뇨증후군 ; 심부전 ; 바소프레신제2수용체 ; 수분 REFERENCES 1. Edelman IS, Leibman J, O Meara MP, Birkenfeld LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 1958;37: Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006;69: Kim GH, Ecelbarger CA, Mitchell C, Packer RK, Wade JB, Knepper MA. Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle's loop. Am J Physiol 1999;276(1 Pt 2):F Furst H, Hallows KR, Post J, et al. The urine/plasma electrolyte ratio: a predictive guide to water restriction. Am J Med Sci 2000;319: Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 1986;314: Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol 1994;4: Ablij HC, Innemee G, Tamsma JT, Meinders AE. Intravenous fluid therapy taken into theoretical and practical consideration: physiology revisited. Neth J Med 2001;58: Nielsen S, Frøkiaer J, Marples D, Kwon TH, Agre P, Knepper MA. Aquaporins in the kidney: from molecules to medicine. Physiol Rev 2002;82: Lehrich RW, Ortiz-Melo DI, Patel MB, Greenberg A. Role of vaptans in the management of hyponatremia. Am J Kidney Dis 2013;62: Miranda CA, Lee JW, Chou CL, Knepper MA. Tolvaptan as a tool in renal physiology. Am J Physiol Renal Physiol 2014; 306:F Manning M, Lammek B, Kolodziejczyk AM, Seto J, Sawyer WH. Synthetic antagonists of in vivo antidiuretic and vasopressor responses to arginine-vasopressin. J Med Chem 1981; 24: Verbalis JG. Vasopressin V2 receptor antagonists. J Mol Endocrinol 2002;29: Ohnishi A, Orita Y, Okahara R, et al. Potent aquaretic agent: a novel nonpeptide selective vasopressin 2 antagonist (OPC ) in men. J Clin Invest 1993;92: Ambrosy A, Goldsmith SR, Gheorghiade M. Tolvaptan for the treatment of heart failure: a review of the literature. Expert Opin Pharmacother 2011;12: Hirano T, Yamamura Y, Nakamura S, Onogawa T, Mori T. Effects of the V(2)-receptor antagonist OPC and the loop diuretic furosemide alone and in combination in rats. J Pharmacol Exp Ther 2000;292:

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