Effects of Exercise on the Expression of 5-HT and TPH in the Raphe Nucles of Autism-treated Rats

Park, Joon-Ki,Lee Sam-Jun 한국스포츠학회 2019 한국스포츠학회지 Vol.17 No.4

임신중 Valproic Acid 투여는 태어난 새씨 쥐에서 자폐증과 같은 행동을 유발한다. 세로토닌은 뇌의 신경 활성을 나타내는 요인으로 뇌의 발달에 중요한 역할을 하는 화학물질이다. 운동은 뇌에서 신경 가소성 및 활성을 증진시키는 요소로 알려져 있다. 본 연구에서는 임신 중 자폐증에 노출된 쥐로부터 태어난 새끼쥐의 봉선핵에서 세로토닌 합성 및 세로토닌 합성을 조절하는 효소인 5-HT 및 TPH의 과-발현증에 수영운동이 미치는 효과를 살펴보았다. 실험결과, 어미 의 자폐증 노출은 새끼 쥐의 봉선핵에서 세로토닌 합성 및 TPH 과발현증으로 불안과 철회행동과 같은 반응을 일으키는 것으로 나타나며, 이러한 반응은 수영 운동을 통해 이와 같은 영향이 억제가 되는 것으로 나타났다. 이와 같은 결과를 바탕으로 수영 운동은 임신 중 자폐증에 노출된 모체로부터 태어난 새끼 쥐들의 5-HT 및 TPH 과-발현증을 감소시킴으 로써 뇌의 기능적인 영향에 유용한 전략적 방안이 될 수 있을 것으로 보여 진다. Using rats exposed prenatally to valproic acid (VPA) as an animal model, we measured expression of 5-HT and TPH in samples collected from the dorsal raphe using the immunohistochemistry. The basal 5-HT and TPH expression level in raphe was significantly higher in VPA-exposed rats relative to controls. Since the over-expression of 5-HT and TPH system is known to be sensitive to physical and psychological stressors, we measured expression 5-HT and TPH levels in raphe nucles after chronic swimming exercise. There were further gradual decreased in hyperserotonemia expression 5-HT and TPH levels during the swimming exercise in the VPA-exposed rats and the level of serotonine decreased in the control rats. The expression 5-HT and TPH revealed a significant decrease in exercise with autism-treated rats. These results suggest that this rodent model of autism exhibits a high expression 5-HT and TPH, which is inhibited by swim exercise. This abnormality may be responsible for anxiety and withdrawal behavior observed in autism. Based on these present results, swimming exercise may be a useful strategy to decrease the hyperserotoninemia such as overexpression 5-HT and TPH of the pups born from mothers who have exposed VPA-treated rats during pregnancy.

Lamotrigine, an antiepileptic drug, inhibits 5-HT3 receptor currents in NCB-20 neuroblastoma cells

김기정,전승현,성기욱 대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.2

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)3 receptors in NCB-20 neuroblastoma cells. Coapplication of lamotrigine (1~300 mM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 mM of 5-HT for an IC50 value of 28.2±3.6 mM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT3-mediated currents evoked by 1 mM dopamine, a partial 5-HT3 receptor agonist, were inhibited by lamotrigine co-application. The EC50 of 5-HT for 5-HT3 receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT3 receptor desensitization, inhibited 5-HT3 receptor currents in a concentration-dependent manner. The deactivation of 5-HT3 receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT3 receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT3 receptor currents. These results indicate that lamotrigine inhibits 5-HT3-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

Lamotrigine, an antiepileptic drug, inhibits 5-HT₃ receptor currents in NCB-20 neuroblastoma cells

Ki Jung Kim,Seung Hyun Jeun,Ki-Wug Sung 대한생리학회-대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.2

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)₃ receptors in NCB-20 neuroblastoma cells. Coapplication of lamotrigine (1~300 μM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 μM of 5-HT for an IC₅₀ value of 28.2±3.6 μM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT₃-mediated currents evoked by 1 mM dopamine, a partial 5-HT₃ receptor agonist, were inhibited by lamotrigine co-application. The EC₅₀ of 5-HT for 5-HT₃ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT₃ receptor desensitization, inhibited 5-HT₃receptor currents in a concentration-dependent manner. The deactivation of 5-HT₃ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT₃ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT₃ receptor currents. These results indicate that lamotrigine inhibits 5-HT₃-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

5-HT 흡수억제성 항우울제들이 가토혈소판의 [$^3H$]Imipramine과 [$^3H$]Paroxetine Binding, [$^3H$]5-HT 흡수, 및 5-HT함량에 미치는 영향

원경식,이민수,신경호,전보권,곽동일,Won, Kyong-Sik,Lee, Min-Soo,Shin, Kyung-Ho,Chun, Boe-Gwun,Kwak, Dong-Il 대한생물정신의학회 1994 생물정신의학 Vol.1 No.1

Many evidences are compatible with the correlation between the inhibition of [$^3H$] imipramine([$^3H$]IMI) and [$^3H$]paroxetine([$^3H$]PAT) binding to the 5-hydroxytryptamine(5-HT) transporter complex and the 5-HT uptake of 5-HT neurons and platelets, and most antidepressants have been shown to inhibit the [$^3H$]IMI and [$^3H$]PAT binding and the neuronal 5-HT uptake. However, several paradoxical research findings led to doubt about the pharmacological significance of the [$^3H$]IMI and [$^3H$]PAT binding sites. This study was carried to clarify the correlation between the [$^3H$]IMI and [$^3H$]PAT binding parameters and the tissue 5-HT content or/and [$^3H$]5-HT uptake in the rabbit platelet, which contains 40 times ad much 5-HT as that of human platelet and shows the 10 fold higher $B_{max}$ of the 5-HT transporter binding to a 5-HT uptake inhibitor. The rabbits were treated for 28 days with amitriptyline(4mg/kg/day : AP), fluoxetine(0.5mg/kg/day : FO), and sertraline(0.5mg/kg/day : SA) via an Alzet osmotic pump implanted for constant infusion. The [$^3H$]IMI binding $B_{max}$ and $K_d$ of the rabbit platelets were $6.4{\pm}1.2$pmol/mg protein and $10.9{\pm}2.1$nM and those in the [$^3H$]PAT binding were $8.6{\pm}1.1$pmol/mg protein and $1.6{\pm}0.3$nM, respectively. AP slightly increased $B_{max}$ of [$^3H$]IMI binding and both [$^3H$]IMI binding and [$^3H$]PAT binding $K_d$, and i contrast, it slightly decreased $B_{max}$ of [$^3H$]PAT binding. FO Slightly increased $K_d$ of both and [$^3H$]IMI and [$^3H$]PAT binding and slightly decreased $B_{max}$ of [$^3H$]IMI and [$^3H$]PAT binding. SA produced the significant increase of [$^3H$]PAT binding $B_{max}$ and the slight increase of both [$^3H$]IMI and [$^3H$]PAT binding $K_d$ and in contrast, it slightly decreased $B_{max}$ and of [$^3H$]IMI binding. And, the $V_{max}$ and $K_m$ of platelet [$^3H$]5-HT uptake were $24.2{\pm}2.4$pmol/$10^8$ platelets/min and $3.3{\pm}0.3$nM, respectively. The $V_{max}$ was little affected by AP, FO, or SA, but the [$^3H$]5-HT uptake $K_m$ value was moderately increased by FO. However, the platelet 5-HT content was moderately decreased by all of the 5-HT uptake inhibitors used in this study. These results seem to be consistent with the allosterical and competitive interaction of 5-HT uptake inhibiting antidepressants with each other as well as 5-HT in the 5-HT transporter binding, and provide no support for the view that the potencies of 5-HT uptake inhibitors to inhibit the [$^3H$]IMI or [$^3H$]PAT binding with 5-HT transporter complex correlate with their antidepressant potencies.

5-HT_1A receptor-mediated activation of G-protein-gated inwardly rectifying K^+ current in rat periaqueductal gray neurons

Jeong, Hyo-Jin,Han, Seung-Ho,Min, Byung-Il,Cho, Young-Wuk 경희대학교 동서의학연구소 2001 東西醫學硏究所 論文集 Vol.2001 No.-

5-Hydroxytryptamine (5-HT) has been reported to modulate analgesia produced by opioids or electrical stimulation of the periaqueductal gray (PAG). 5-HT increases K^+ conductance and inhibits the firing activity of the PAG neurons. We examined the electrophysiological and pharmacological characteristics of the K^+ current involved in 5-HT-induced hyperpolarization of dissociated rat PAG neurons. Among the neurons tested, 5-HT activated inward K^+ currents in 30-40%, whilst the remaining 60-70% did not respond to 5-HT. 5-HT activated an inwardly rectifying K^+ current (I_5-HT) in a concentration- and voltage-dependent manner. I_5-HT was mimicked by a 5-HT_1A receptor selective agonist, 8-OH-DPAT, and was reversibly blocked by a 5-HT_1A receptor antagonist, piperazine maleate, but not by a 5-HT_2 receptor antagonist, ketanserin. I_5-HT was sensitive to K^+ channel blockers such as quinine and Ba^2+, but insensitive to 4-aminopyridine, Cs^+ and tetraethylammonium I_5-HT was inhibited by GDPβs and was irreversibly activated by GTPγs. I_5-HT was significantly suppressed by N-ethylmaleimide and pertussis toxin, but not by cholera toxin. Second messenger modulators such as staurosporin, forskolin, and phorbol-12-myristate-13-acetate did not alter I_5-HT. the present study indicates that 5-HT-induced hyperporlarization of the PAG neurons results from activation of the pertussis toxin-sensitive G-proteincoupled inwardly rectifying K^+ currents through 5-HT_1A receptors. ⓒ 2001 Elsevier Science Ltd. All rights reserved.

Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice

Jiang, Shu-Heng,Li, Jun,Dong, Fang-Yuan,Yang, Jian-Yu,Liu, De-Jun,Yang, Xiao-Mei,Wang, Ya-Hui,Yang, Min-Wei,Fu, Xue-Liang,Zhang, Xiao-Xin,Li, Qing,Pang, Xiu-Feng,Huo, Yan-Miao,Li, Jiao,Zhang, Jun-Feng Elsevier 2017 Gastroenterology Vol.153 No.1

<P><B>Background & Aims</B></P> <P>Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors.</P> <P><B>Methods</B></P> <P>We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from Kras<SUP>G12D/+</SUP>/Trp53<SUP>R172H/+</SUP>/Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses.</P> <P><B>Results</B></P> <P>In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B–LYN–p85 complex, which increased PI3K–Akt–mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice.</P> <P><B>Conclusions</B></P> <P>Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.</P>

뇌실내 TFMPP가 가토신장기능에 미치는 효과

임영채(Young Chai Lim),최종범(Johng Bom Choi),김경근(Kyung Keun Kim),국영종(Young Johng Kook) 대한약리학회 1992 대한약리학잡지 Vol.28 No.2

신장기능조절에 있어서 중추 tryptamine계가 관련되어 있으며, 5-HT₁수용체는 이뇨적인 역할을 하고 있는 반면에 5-HT₂ 및 5-HT₃수용체는 항이뇨적인 영향을 미치고 있음이 밝혀진 바 있다. 또한 5-HT₁수용체도 단일하지 않고 여러 subtype가 존재함이 알려져 있다. 5-HT_1A수용체의 역할에 관해서는 신기능에 이뇨적인 영향을 미치고 있음이 시사된 바 있다. 본 연구에서는 중추 tryptamine성 신기능 조절에 있어서 5-HT_1B수용체의 역할을 구명하고자 하였다. 선택적 5-HT_1B agonist인 TFMPP 8 ~ 750μg/kg을 가토 측뇌실내로 투여하면 투여량에 비례하여 이뇨 및 Na과 K 배설의 증가를 초래하였으며, 250μg/kg 투여시에는 Na의 배설 분획이 5.44%까지 증가하였다. Na배설 촉진작용은 신혈류역학의 증가 보다도 훨씬 지속하여, 세뇨관에서의 Na재흡수 감소작용이 체액성 기전임을 시사하였다. TFMPP 250μg/kg icv투여시에 natriuresis와 함께 혈장내 atrial natriuretic peptide 농도가 약 6배 증가되었다. TFMPP 250μg/kg을 정맥내로 투여하였을때는 뇌실내 투여시와는 상이하게 신기능에 별다른 유의한 변동을 초래하지 않았다. 이와같은 TFMPP의 diuresis 및 natriuresis는 각각 5-HT₂ 및 5-HT₃ 수용체의 선택적 antagonist인 ketanserin과 MDL 72222의 전처치에 의하여 차단되지 않았으며, methysergide에 의해서도 억제되지 않았다. 또한 5-HT_1A antagonist로 알려진 NAN-190도 TFMPP의 작용을 차단하지 못하였으며 S(-)-propranolol도 영향을 미치지 않았다. 본 연구의 결과 중추 5-HT_1B수용체는 신장기능에 이뇨 및 Na배설 촉진적인 영향을 미치고 있고 이작용에 atrial natriuretic peptide가 관여함을 알 수 있었다. The central tryptaminergic system has been shown to play an important role in the regulation of renal function: 5-HT₁ receptor mediate diuresis and natriuresis, whereas both 5-HT₂ and 5-HT₃ mediate antidiuresis and antinatriuresis. Recently, 5-HT₁ receptors are further subdivided into many subtypes, and central 5-HT_1A subtype was shown to mediate diuretic and natriuretic effects. The present study was undertaken to delineate the role of 5-HT_1B subtype. Trifluoromethylphenylpiperazine (TFMPP), a selective 5-HT_1B agonist in doses ranging from 8 to 750μg/kg icv elicited diuresis, natriuresis and kaliuresis in dose-dependent fashion, with the fractional excretion of filtered Na reaching 5.44% with 250μg/kg icv. The natriuresis outlasted the transient increases in renal hemodynamics, suggesting humoral mediation in the decreased tubular Na reabsorption. Plasma concentration of atrial natriuretic peptide increased along with the natriuresis. Systemic blood pressure transiently increased. When given intravenously, no diuresis and natriuresis was elicited, indicating the central mechanism. The icv TFMPP effects were not significantly affected by icv methysergide, a nonselective 5-HT₁ blocker. Both ketanserin and MDL 72222, selective 5-HT₂ and 5-HT₃ antagonists, resp., did not abolish the TFMPP effects. Nor did NAN-190, 5-HT_1A blocker, affect the TFMPP effects. These observations suggest that central 5-HT_1Breceptors may play a role in the central regulation of renal function by exerting diuretic and natriuretic influences, mainly through natriuretic factors.

Lamotrigine, an antiepileptic drug, inhibits 5-HT₃ receptor currents in NCB-20 neuroblastoma cells

Kim, Ki Jung,Jeun, Seung Hyun,Sung, Ki-Wug The Korean Society of Pharmacology 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.2

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine $(5-HT)_3$ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine ($1{\sim}300{\mu}M$) resulted in a concentration-dependent reduction in peak amplitude of currents induced by $3{\mu}m$ of 5-HT for an $IC_{50}$ value of $28.2{\pm}3.6{\mu}M$ with a Hill coefficient of $1.2{\pm}0.1$. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, $5-HT_3$-mediated currents evoked by 1 mM dopamine, a partial $5-HT_3$ receptor agonist, were inhibited by lamotrigine co-application. The $EC_{50}$ of 5-HT for $5-HT_3$ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate $5-HT_3$ receptor desensitization, inhibited $5-HT_3$ receptor currents in a concentration-dependent manner. The deactivation of $5-HT_3$ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of $5-HT_3$ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the $5-HT_3$ receptor currents. These results indicate that lamotrigine inhibits $5-HT_3$-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

가토신장기능에 미치는 뇌실내 Ketanserin의 영향

국영종(Young Johng Kook),김경근(Kyung Keun Kim),임영채(Young Chai Lim),김유남(Yoo Nam Kim),국훈(Hoon Kook) 대한약리학회 1990 대한약리학잡지 Vol.26 No.2

5-Hydroxytryptamine(5-HT)를 가토뇌실내로 투여 (icv)하면 이뇨와 Na배설증가가 초래되며, 이러한 작용은 5-HT₁ 수용체길항제인 methysergide에 의하여 차단되므로 중추성 신장기능조절에 있어 중추 tryptamine계의 관련이 시사된 바 있다. 본 연구에서는 5-HT₂ 길항제로 알려진 ketanserin (KET)를 이용하여 5-HT₂ 수용체의 역할을 구명하고자 하였다. KET 120μg(=0.3μmoles)/kg icv는 신혈류역학에는 아무런 변동을 일으키지않으나 유의한 Na배설증가를 초래하여, 세뇨관에서의 Na 재흡수 감소가 시사되었다. 전신혈압은 약간 감소하였다. 정맥내 투여시에는 유의한 기능변동을 볼 수 없었다. 5-HT 200μg/kg icv는 경미하나 유의한 Na배설증가 및 이뇨작용을 나타냈다. 그러나 신장기능에 그다지 큰 영향을 미치지 않는 양인 40μg/kg의 KET icv후에는 5-HT의 작용이 크게 강화되어, Na배설분획이 9.3%에 달하였다. Norepinephrine, dopamine, histamine과 같은 다른 생체아민의 신장작용은 KET전처치에 의하여 영향받지 아니하였다. 본 연구는 중추 5-HT₁ 수용체와는 반대로 중추 5-HT₂ 수용체는 항이뇨 및 Na배설감소를 매개하고 있으며, 중추 tryptamine계는 신장기능을 이중적으로 조절하고 있음을 시사하였다. 5-Hydroxytryptamine (5-HT) was reported to elicit natriuresis and diuresis when given intracerebroventricularly (icv) and these effects were shown to be abolished by icv methysergide, 5-HT₁ antagonist, thus suggesting that central tryptaminergic system may also participate in the regulation of renal function. We tried in this study to elucidate the role of 5-HT₂ receptors in the central tryptaminergic regulation of renal function, observing the effects of icv ketanserin, a specific 5-HT₂ antagonist. Ketanserin (KET) icv in doses of 120μg (=0.3μmoles)/kg produced significant natriuresis without affecting renal hemodynamics, indicating that it resulted from decreased tubular Na reabsorption. Systemic blood pressure decreased slightly but significantly. When given iv, no significant effect was observed. 5-HT, 200μg/kg icv, produced mild but significant natriuresis and diuresis. However, after KET, 40μ g/kg icv, a dose which minimally affects renal function, the natriuresis and diuresis by 5-HT was greatly augmented, with the fractional excretion of filtered sodium reaching 9.3%. The renal effects of other biogenic amines administered icv, such as norepinephrine, dopamine and histamine, were not significantly affected by the KET pretreatment. These observations suggest that central tryptaminergic system influences renal function in dual ways, i.e., natriuretic and diuretic influence via 5-HT₁ receptors, whereas 5-HT₂ subtypes mediate the antinatriuretic and antidiuretic effects, and that the central tryptaminergic system plays a role in the regulation of rabbit renal function.

Influence of Intracerebroventricular Ketanserin on Rabbit Renal Function

국영종,김경근,임영채,김유남,국훈,Kook, Young-Johng,Kim, Kyung-Keun,Lim, Young-Chai,Kim, Yoo-Nam,Kook, Hoon The Korean Society of Pharmacology 1990 대한약리학잡지 Vol.26 No.2

5-Hydroxytryptamine(5-HT)를 가토뇌실내로 투여 (icv)하면 이뇨와 Na배설증가가 초래되며, 이러한 작용은 $5-HT_1$ 수용체길항제인 methysergide에 의하여 차단되므로 중추성 신장기능조절에 있어 중추 tryptamine계의 관련이 시사된 바 있다. 본 연구에서는 $5-HT_2$ 길항제로 알려진 ketanserin (KET)를 이용하여 $5-HT_2$ 수용체의 역할을 구명하고자 하였다. KET $120\;{\mu}g(=0.3{\mu}moles)/kg$ icv는 신혈류역학에는 아무런 변동을 일으키지않으나 유의한 Na배설증가를 초래하여, 세뇨관에서의 Na 재흡수 감소가 시사되었다. 전신혈압은 약간 감소하였다. 정맥내 투여시에는 유의한 기능변동을 볼 수 없었다. 5-HT $200{\mu}g/kg$ icv는 경미하나 유의한 Na배설증가 및 이뇨작용을 나타냈다. 그러나 신장기능에 그다지 큰 영향을 미치지 않는 양인 $40{\mu}g/kg$의 KET icv후에는 5-HT의 작용이 크게 강화되어, Na배설분획이 9.3%에 달하였다. Norepinephrine, dopamine, histamine과 같은 다른 생체아민의 신장작용은 KET전처치에 의하여 영향받지 아니하였다. 본 연구는 중추 $5-HT_1$ 수용체와는 반대로 중추 $5-HT_2$ 수용체는 항이뇨 및 Na배설감소를 매개하고 있으며, 중추 tryptamine계는 신장기능을 이중적으로 조절하고 있음을 시사하였다. 5-Hydroxytryptamine (5-HT) was reported to elicit natriuresis and diuresis when given intracerebroventricularly (icv) and these effects were shown to be abolished by icv methysergide, $5-HT{_1}$ antagonist, thus suggesting that central tryptaminergic system may also participate in the regulation of renal function. We tried in this study to elucidate the role of $5-HT_2$ receptors in the central tryptaminergic regulation of renal function, observing the effects of icv ketanserin, a specific $5-HT_2$ antagonist. Ketanserin (KET) icv in doses of $120{\mu}g$ $(=0.3\;{\mu}moles)/kg$ produced significant natriuresis without affecting renal hemodynamics, indicating that it resulted from decreased tubular Na reabsorption. Systemic blood pressure decreased slightly but significantly. When given iv, no significant effect was observed. 5-HT, $200{\mu}g/kg$ icv, produced mild but significant natriuresis and diuresis. However, after KET, $40{\mu}\;g/kg$ icv, a dose which minimally affects renal function, the natriuresis and diuresis by 5-HT was greatly augmented, with the fractional excretion of filtered sodium reaching 9.3%. The renal effects of other biogenic amines administered icv, such as norepinephrine, dopamine and histamine, were not significantly affected by the KET pretreatment. These observations suggest that central tryptaminergic system influences renal function in dual ways, i.e., natriuretic and diuretic influence via $5-HT_1$ receptors, whereas $5-HT_2$ subtypes mediate the antinatriuretic and antidiuretic effects, and that the central tryptaminergic system plays a role in the regulation of rabbit renal function.