Interrelationship Between Clonidine-Induced Hypotension and Opiate Receptors in Rabbits

Lim, Dong-Yoon,Hwang, Chi-Won,Kim, Bong-Han,Yoon, Joong-Keun,Lee, Jong-Jin,Kang, Tae-Joon,Choi, Cheol-Hee 朝鮮大學校 附設 醫學硏究所 1992 The Medical Journal of Chosun University Vol.17 No.1

Clonidine은 특히 중추에서 adrenergic alpha₂-receptor의 효능약으로 카테콜아민의 유리를 억제하므로써 혈압강하제로 상용되는 약물이다. Urethane 마취 가토를 이용하여 clonidine 의 혈압하강 반응 및 심박감소 반응에 대한 opiate 수용체와의 상관성을 관찰하기 위하여 본 연구를 시행하여 얻어진 결과는 다음과 같다. Clonidine(5-20ug/㎏)을 가토의 대퇴정맥내로 투여시 용량의존성의 현저한 혈압하강 및 심박감소 반응을 나타내었다. 또한 Clonidine(2.5-10ug)을 측뇌실내로 투여시에도 용량의존성의 유의성인 혈압 하강 및 심박감소 작용을 나타내었다. Opiate 수용체 길항약인 naloxone(30ug /㎏/30min)을 정 내로 전처치한 다음에는 clonidine의 정맥 및 측뇌실내 투여에 의한 혈압강하 및 심박감소 반응이 뚜렷이 억제 되었다. 측뇌실내로 naloxone(8ug)을 투여한 후에도 정맥 및 측뇌실내 clonidine으로 나타나는 혈압하강 및 심박감소 작용이 현저하게 감약되었다. 본 연구에서 사용된 용량에서 naloxone은 측뇌실내 및 정맥내에 투여시 혈압 및 심박에 별다른 영향을 미치지 못했었다. 이상과 같은 연구결과로 보아 clonidine의 혈압하강 및 심박감소 작용은 적어도 opiate 수용체의 활성화를 통해서 나타나는 것으로 사료된다. The present investigation was designed to examine the interrelationship between clonidine-induced hypotension and opiate receptors in the urethane-anesthetized rabbits. Clonidine (5-20ug / kg) given into a femoral vein of the rabbit produced a dose-related, marked fall in arterial blood pressure and a reduction in heart rate. Intraventricular clonidine (2.5-10ug) caused dose-dependent and significant hypotensive and bradycardic responses. Intravenous naloxone (30ug / kg / 30min), an opiate receptor antagonist, when given prior to c1onidine, prevented significantly hypotensive and bradycardic responses induced by introvenous of intraventricular clonidine. Naloxone injected into a lateral ventricle before clonidine administration inhibited greatly intravenous and intraventricular clonidine-evoked depressor and bradycardia. Both intravenous and intraventricular naloxone at doses used in the present study did not affect arterial blood pressure and heart rate, suggesting that naloxone increases sympathetic nerve activity peripherally, and may abolish clonidine-induced depressor and bradycardia by also increasing sympathetic activity in the central nervous system through blockade of opiate receptors. From the present experimental data, it. is considered that the hypotensive and bradycardic effect of clonidine may be mediated at least partly through interactions with endogenous opiate peptides.

Effects of clonidine on the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes

우재희,한종인,백희정,이희승 대한마취통증의학회 2012 Korean Journal of Anesthesiology Vol.62 No.3

Background: Clonidine has been shown to be a potent neuroprotectant by acting at α2 receptors on glutamatergic neurons to inhibit the release of glutamate. The aim of this study is to investigate the effects of clonidine on the activity of EAAT3 that can regulate extracellular glutamate. Methods: EAAT3 was expressed in the Xenopus oocytes. Using a two-electrode voltage clamp, membrane currents were recorded after application of 30 μM L-glutamate both in the presence and absence of various concentrations of clonidine. To determine the effects of clonidine on the Km and Vmax of EAAT3 and the reversibility of clonidine effects, membrane currents were recorded after the application of various concentrations of L-glutamate both in the presence and absence of 1.50 × 10-7 M clonidine. Results: Clonidine reduced the EAAT3 responses to L-glutamate in a concentration-dependent manner. This inhibition was statistically significant at higher concentrations than at the clinically relevant range. Clonidine at 1.50× 10-7 M reduced the Vmax, but did not affect the Km of EAAT3 for L-glutamate. Conclusions: These results suggest that the direct inhibition of EAAT3 activity is not related to the sedation effect of clonidine and that the clonidine-induced reduction of EAAT3 activity provides additional data for the possible involvement of glutamatergic hyperactivity in the proconvulsant effect of clonidine. Background: Clonidine has been shown to be a potent neuroprotectant by acting at α2 receptors on glutamatergic neurons to inhibit the release of glutamate. The aim of this study is to investigate the effects of clonidine on the activity of EAAT3 that can regulate extracellular glutamate. Methods: EAAT3 was expressed in the Xenopus oocytes. Using a two-electrode voltage clamp, membrane currents were recorded after application of 30 μM L-glutamate both in the presence and absence of various concentrations of clonidine. To determine the effects of clonidine on the Km and Vmax of EAAT3 and the reversibility of clonidine effects, membrane currents were recorded after the application of various concentrations of L-glutamate both in the presence and absence of 1.50 × 10-7 M clonidine. Results: Clonidine reduced the EAAT3 responses to L-glutamate in a concentration-dependent manner. This inhibition was statistically significant at higher concentrations than at the clinically relevant range. Clonidine at 1.50× 10-7 M reduced the Vmax, but did not affect the Km of EAAT3 for L-glutamate. Conclusions: These results suggest that the direct inhibition of EAAT3 activity is not related to the sedation effect of clonidine and that the clonidine-induced reduction of EAAT3 activity provides additional data for the possible involvement of glutamatergic hyperactivity in the proconvulsant effect of clonidine.

실험적 고혈압 백서의 심맥관계 기능조절에 있어서 중추 Opiate System의 역할

김기원(Kee-Won Kim),곽용근(Yong-Geun Kwak),채준석(Joon-Seak Chae),조규박(Kyu-Park Cho) 대한약리학회 1987 대한약리학잡지 Vol.23 No.2

Morphine을 비롯한 opioid peptide가 말초 또는 중추에 투여시 혈압하강과 심박동수감소를 보이며 opiate 수용체 길항제인 naloxone에 의해 길항됨이 관찰되었던바 근래 몇몇 보고들은 중추신경내에서 adrenergic및 opioidergic system이 서로 관련되어 있음을 시사하고 있다. 이에 본 실험에서 고혈압 연구에 널리 사용되고 있는 2-kidney, 1-clip (2K1C) 방법으로 실험적 고혈압을 유발시킨 백서의 측뇌실내 clonidine또는 morphine의 심맥관계에 대한 효과와 각각의 차단제에 의한 영향 그리고 정상 및 고혈압상태 백서의 뇌내 β-endorphin의 함량과 specific opiate receptor binding을 정량하여 고혈압 유발에 따른 뇌내 opiate system의 변동을 관찰하였다. 2K1C 고혈압 또는 sham-operated대조백서에서 측뇌실내 clonidine (3-30μg/kg)은 용량에 비례하여 혈압하강과 심박동수감소를 일으켰으며 clonidine의 혈압강하 효과는 2K1C고혈압 백서에서 더욱 현저하였다. clonidine의 혈압강하효과는 고혈압 백서에서 측뇌실내 yohimbine 또는 naloxone 전처리에 의해 약화되었고 대조군에서는 yohimbine (30μg/kg, i.v.t.)에 의해 억제되었으나 naloxone (50μg/kg, i.v.t.)에 의해서는 영향 받지 않았다. clonidine과 마찬가지로 측뇌실내 morphine (10-100μg/kg)은 2K1C 고혈압 또는 sham-operated 대조백서에서 용량에 비례하여 혈압하강과 심박동수감소를 일으켰으며, morphine의 혈압강하효과는 2K1C 고혈압백서에서 더욱 현저하였다. 대조군과 고혈압군에서 morphine의 혈압강하효과는 naloxone 전처리에 의해 현저히 약화되었으나 yohimbine에 의해서는 영향 받지 않았다. 2K1C 시술익일부터 투여한 clonidine은 2K1C 시술에 의한 혈압 상승을 억제하였으며 naloxone (2 mg/kg, i.p.)에 의해 반전되었다. 2K1C 시술에 의해 고혈압이 유발된 백서의 뇌내 β-endorphin 함량은 sham-operated 군에 비하여 유의하게 감소되어 있었고 (3H)-naloxone의 specific binding의 Bmax는 증가되었으나 Kd치는 변동되지 않았다. 이상의 실험 성적은 뇌내 opiate계가 혈압조절에 중요한 역할을 담당하고 있으며 2K1C 고혈압백서의 고혈압상태 유지에 뇌내 opiate계의 기능저하가 일부관여하고 있음을 강력히 시사한다. The possible inolvement of central opiate system in the control of cardiovascular function and in the antihypertensive action of clonidine has been examined in unanesthetized rats with shamoperated or 2-kidney, 1-clip (2K1C) renal hypertension. In both groups of rats, intraventricular clonidine (3-30μg/kg) produced hypotension and bradycardia. Hypotensive action of clonidine was more potent in the hypertensive rats than in the normotensive sham-operated rats. Yohimbine (30μg/kg, i.v.t.) inhibited the hypotension and bradycardia produced by clonidine. Naloxone (50μg/kg, i.v.t.) inhibited the action of clonidine in 2K1C hypertensive rats but not influenced in the sham-operated rats. Intraventricular morphine (10-100μg/kg) also reduced rats. Intraventricular morphine (10-100μg/kg) also reduced blood pressure and heart rate in both groups of rats. But these effects were not affected by yohimbine, but antagonized by naloxone (50μg/kg, i.v.t.). Chronic treatment of 2K1C rats with clonidine (3 X 20μg/kg, p.o.,) for 14 days from 1 day after 2K1C operation) suppressed the development of hypertension and maintained the blood pressure in normal level and this errect of clonidine was abolished by naloxone (2 mg/kg, i. p.). In the 2K1C hypertensive rats, immunoreactive β-endorphin content was significantly decreased, but maximum binding (Bmax) of (³H)-naloxone was significantly increased in brain of 2K1C hypertensive rats. However, Kd value was not changed. These results suggest that the opioidergic component might be involved in the antihypertensive action of clonidine only in hypertensive and that central opiate system might play important roles in pathophysiology of development and maintenance of hypertension.

Role of Central opiate System in Control of Cardiovascular Function of Experimental Hypertensive Rats

김기원,곽용근,채준석,조규박,Kim, Kee-Won,Kwak, Yong-Geun,Chae, Joon-Seak,Cho, Kyu-Park The Korean Society of Pharmacology 1987 대한약리학잡지 Vol.23 No.2

Morphine을 비롯한 opioid peptide가 말초 또는 중추에 투여시 혈압하강과 심박동수감소를 보이며 opiate 수용체 길항제인 naloxone에 의해 길항됨이 관찰되었던바 근래 몇몇 보고들은 중추신경내에서 adrenergic및 opioidergic system이 서로 관련되어 있음을 시사하고 있다. 이에 본 실험에서 고혈압 연구에 널리 사용되고 있는 2-kidney, 1-clip (2K1C) 방법으로 실험적 고혈압을 유발시킨 백서의 측뇌실내 clonidine또는 morphine의 심맥관계에 대한 효과와 각각의 차단제에 의한 영향 그리고 정상 및 고혈압상태 백서의 뇌내 ${\beta}-endorphin$의 함량과 specific opiate receptor binding을 정량하여 고혈압 유발에 따른 뇌내 opiate system의 변동을 관찰하였다. 2K1C 고혈압 또는 sham-operated대조백서에서 측뇌실내 clonidine $(3-30\;{\mu}g/kg)$은 용량에 비례하여 혈압하강과 심박동수감소를 일으켰으며 clonidine의 혈압강하 효과는 2K1C고혈압 백서에서 더욱 현저하였다. clonidine의 혈압강하효과는 고혈압 백서에서 측뇌실내 yohimbine 또는 naloxone 전처리에 의해 약화되었고 대조군에서는 yohimbine ($30\;{\mu}g/kg$, i.v.t.)에 의해 억제되었으나 naloxone ($50\;{\mu}g/kg$, i.v.t.)에 의해서는 영향 받지 않았다. clonidine과 마찬가지로 측뇌실내 morphine $(10-100\;{\mu}g/kg)$은 2K1C 고혈압 또는 sham-operated 대조백서에서 용량에 비례하여 혈압하강과 심박동수감소를 일으켰으며, morphine의 혈압강하효과는 2K1C 고혈압백서에서 더욱 현저하였다. 대조군과 고혈압군에서 morphine의 혈압강하효과는 naloxone 전처리에 의해 현저히 약화되었으나 yohimbine에 의해서는 영향 받지 않았다. 2K1C 시술익일부터 투여한 clonidine은 2K1C 시술에 의한 혈압 상승을 억제하였으며 naloxone (2 mg/kg, i.p.)에 의해 반전되었다. 2K1C 시술에 의해 고혈압이 유발된 백서의 뇌내 ${\beta}-endorphin$ 함량은 sham-operated 군에 비하여 유의하게 감소되어 있었고 (3H)-naloxone의 specific binding의 Bmax는 증가되었으나 Kd치는 변동되지 않았다. 이상의 실험 성적은 뇌내 opiate계가 혈압조절에 중요한 역할을 담당하고 있으며 2K1C 고혈압백서의 고혈압상태 유지에 뇌내 opiate계의 기능저하가 일부관여하고 있음을 강력히 시사한다. The possible inolvement of central opiate system in the control of cardiovascular function and in the antihypertensive action of clonidine has been examined in unanesthetized rats with shamoperated or 2-kidney, 1-clip (2K1C) renal hypertension. In both groups of rats, intraventricular clonidine $(3-30\;{\mu}g/kg)$ produced hypotension and bradycardia. Hypotensive action of clonidine was more potent in the hypertensive rats than in the normotensive sham-operated rats. Yohimbine $(30\;{\mu}g/kg,\;i.v.t.)$ inhibited the hypotension and bradycardia produced by clonidine. Naloxone ($50\;{\mu}g/kg$, i.v.t.) inhibited the action of clonidine in 2K1C hypertensive rats but not influenced in the sham-operated rats. Intraventricular morphine $(10-100\;{\mu}g/kg)$ also reduced rats. Intraventricular morphine $(10-100\;{\mu}g/kg)$ also reduced blood pressure and heart rate in both groups of rats. But these effects were not affected by yohimbine, but antagonized by naloxone ($50\;{\mu}g/kg$, i.v.t.). Chronic treatment of 2K1C rats with clonidine ($3{\times}20\;{\mu}g/kg$, p.o.,) for 14 days from 1 day after 2K1C operation) suppressed the development of hypertension and maintained the blood pressure in normal level and this errect of clonidine was abolished by naloxone (2 mg/kg, i. p.). In the 2K1C hypertensive rats, immunoreactive ${\beta}-endorphin$ content was significantly decreased, but maximum binding (Bmax) of $(^3H)-naloxone$ was significantly increased in brain of 2K1C hypertensive rats. However, Kd value was not changed. These results suggest that the opioidergic component might be involved in the antihypertensive action of clonidine only in hypertensive and that central opiate system might play important roles in pathophysiology of development and maintenance of hypertension.

미추 마취시 국소마취제에 첨가한 Clonidine과 Epinephrine의 효과 비교

이상길,김시오,임동건,홍정길,박진웅,김병권 慶北大學校 醫科大學 1996 慶北醫大誌 Vol.37 No.2

목적 : 경막외로 투여한 clonidine과 epinephrine은 진통작용 뿐만 아니라 국소마취제의 효과를 증진시킨다. Clonidine의 진통효과는 척수내의 presynaptic and postsynaptic α_2 -adrenoceptor에 의한 통증 신호를 차단함으로 이루어지며, 또한 용량에 따라서 혈압과 맥박수를 떨어뜨리기도 한다. 이 연구의 목적은 clonldine과 epinephrine을 미추 마취시 투여하여 진통 지속시간과 혈역학적인 변화를 관찰하기 위함이다. 대상 및 방법 : 미국 마취과학회 분류 1급 및 2급에 해당하는 47명의 환자를 대상으로 하였다. 미추 마취시 clonidine(2㎍/㎏), lidocaine(20c.c.), bivon®(1.5c.c.)을 투여한 군은 28명이었으며, clonidine 대신 epinephrine(0.1c.c.)을 투여한 군은 19명이었다. Clonidine군과 epinephrine군의 혈역학적 변화는 초기와 35분동안 5분 간격으로 혈압과 맥박수를 비교하였으며, 진통지속 시간의 비교는 5point verbal scale(1 ; comfortable, 2 ; mildly uncomfortable, 3 ; very uncomfortable, 4 ; In pain, 5 ; in bad pain)을 사용하여 4번에 해당할 때까지의 시간을 기준으로 하였다. 결과 : 두 군간에 혈역학적인 변화는 유의한 차이가 없었으며, 진통지속시간에 있어서는 epinephrine군은 202±52분, clonidine군은 237±44분으로 통계학적인 의의가 있었다(p<0.05). 결론 : 미추마취시 epinephrine 대신 clonidine(2㎍/㎏)의 사용은 특별한 혈역학적인 변화 없이 진통지속시간의 연장에 도움이 된다. Background : Epidural clonidine is reported to produce analgesia in human and to prolong analgesic action of local anesthetics. Epidural epinephrine is also above. Clonidine blocks transmission of pain information by activating presynaptic and postsynaptic α_2-adrenoceptors in the spinal cord. Clonidine also produced dose dependent decreases in blood pressure and heart rate. We were to evaluate the differance of analgesic duration and hemodynamic changes between clonidine and epinephrine which additived to local anesthetics during caudal anesthesia. Method : The patients' number is 47 cases(ASA class Ⅰ and Ⅱ). Clonidine group(N=28) received clonidine(2㎍/㎏), lidocaine(20cc), bivon(1.5cc) and epinephrine group (N=19) received epinephrine(0.1cc), lidocaine(20cc) and bivon(1.5cc.). We measured blood pressure and heart rate to compare clonidine and epinephrine group for 35 minutes. We used 5 point verbal scale(1 ; comfortable, 2 ; mildly uncomfortable, 3 ; very uncomfortable, 4 ; in pain, 5 ; in bad pain) to compare analgesic duration between clonidine and epinephrine group and considered the analgesic duration when the verbal scale reached number 4. Results : There were no significant difference in hemodynamic changes between two groups. The duration of analgesia in clonidine group showed significant longer (p<0.05) than epinephrine group. Epinephrine group is 202±52 minutes and clonidine group is 237±44 minutes. Conclusion : We concluded that caudal clonidine(2㎍/㎏) has longer analgesic duration than caudal epinephrine without remarkable hemodynamic changes.

수영(水泳)-스트레스에 의한 혈장 Corticosterone 함량 및 뇌(腦) Catecholamine대사(代謝)의 변동(變動)에 미치는 Thyroxine 및 Propylthiouracil의 영향

신경호(Kyung-Ho Shin),홍기남(Ki-Nam Hong),김형건(Hyung-Gun Kim),전보권(Boe-Gwun Chun) 대한약리학회 1989 대한약리학잡지 Vol.25 No.1

수영-스트레스로 나타나는 뇌 catecholamine대사 및 혈장 corticosterone 함량의 변동에 대한 clonidine(500 ug/kg)의 억제작용을 propylthiouracil(0.01% 용액으로 5주간 마시게함) 및 1-thyrorine(4 mg/kg/day로 5일간 복강내에 주사)로 처치한 웅성-마우스에서 실험관찰하여 다음과 같은 성적을 얻었다. 마우스의 일과성 자발운동량의 변동은 갑상선-홀몬의 변동에 영향을 받지 않았고, 수영스트레스(SS)로 나타나는 혈장 corticosterone(CS)의 증가가 propylthiouracil 전처치 (PTU) 및 1-thyroxine 전처치 (T4)로 각각 다소의 감소 및 증강됨을 보였으나, SS에 의한 혈장 CS증가에 대한 clonidine의 억제작용은 PTU 및 T4의 영향을 받지 않았다. SS부하로 뇌 3-methoxy-4-hydroxyphenylglycol 함량(MHPG)가 유의하게 증가되고 clonidine에 의하여는 MHPG가 현저히 감소되었으나 뇌 norepinephrine 함량(NE)은 별 변동을 보이지 않아서 MHPG/NE비는 SS와 clonidine에 의하여 각각 현저한 증가 및 감소를 나타내었다. 아울러, PTU및 T4은 각각 뇌NE을 유의하게 감소 또는 증가시켰으나 뇌 MHPG에는 별 영향을 미치지 않았다. Clonidine은 SS에 의한 뇌 MHPG 및 MHPG/NE비의 증가를 모두 현저히 억제하였으며 그 억제작용은 PTU 및 T4에 의하여 별 영향을 받지 않았다. 이상의 성적으로 미루어서, 마우스의 일과성 자발운동양상 및 스트레스반응으로 나타나는 혈장 corticosterone의 증가현상등이 갑상선-홀몬의 변동에 별 영향을 받지 않으며, 시상하부-뇌하수체-부신계의 활성화가 시상하부의 norepinephrine성 신경-흥분에 매게되어 나타나는 바, 스트레스성 혈장 corticosterone 증가에 대한 clonidine의 억제작용이 그의 절전-α₂-adrenoceptor agonist 작용에 기인되는 것으로 사료된다. The circadian rhythm of spontaneous motor activity was not significantly altered by T₄(4mg/kg, i.p. inj. once a day for 5 days: T₄) and PTU (fed ad lib in 0.01% drinking water for 5 weeks: PTU). The plasma thyroxine level was markedly increased by T₄ but reduced by PTU, and the plasma thyrotropin level was markedly increased by PTU but moderately increased by T₄. Clonidine slightly increased the plasma CS level, but the clonidine effect was significantly enhanced by T₄-pretreatment. The brain NE and MHPG contents were little affected by T₄ but the NE content was significantly decreased by PTU. The SS-induced increase of plasma CS level was moderately decreased by PTU but increased by T₄. However, clonidine significantly inhibited the SS-induced increase, and the inhibitory effect of clonidine was not significantly affected by PTU and T₄, respectively. The brain MHPG content and MHPG/NE ratio were significantly decreased by clonidine but increased by SS. The clonidine- and SS-induced changes of brain MHPG content and MHPG/NE ratio were not altered by T₄. PTU did not affect the SS-induced increase of brain NE turnover but significantly attenuated the clonidine-induced decrease. The SS-induced increases of brain MHPG content and MHPG/NE rtatio were markedly inhibited by clonidine, and the inhibitory effect of clonidine was not affected by T₄ and PTU, respectively. These results suggest that the responses to swim-stress is not signigicantly affected by the alteration of thyroid function and that the hypothalamo-adenohypophysis-adrenocortical stimulation in response to swim-stress seems to be mediated via hypothalamic noradrenergic activation, and the stress response may be inhibited by the agonistic activity of clonidine on the presynaptic α₂-adrenoceptor.

Effect of Thyroxie and Propylthiouracil on the Responses of Plasma Corticosterone and Brain Norepinephrine to Swim-Stress

신경호,홍기남,김형건,전보권,Shin, Kyung-Ho,Hong, Ki-Nam,Kim, Hyung-Gun,Chun, Boe-Gwun The Korean Society of Pharmacology 1989 대한약리학잡지 Vol.25 No.1

수영-스트레스로 나타나는 뇌 catecholamine대사 및 혈장 corticosterone 함량의 변동에 대한 clonidine(500 ug/kg)의 억제작용을 propylthiouracil(0.01% 용액으로 5주간 마시게함) 및 1-thyrorine(4 mg/kg/day로 5일간 복강내에 주사)로 처치한 웅성-마우스에서 실험관찰하여 다음과 같은 성적을 얻었다. 마우스의 일과성 자발운동량의 변동은 갑상선-홀몬의 변동에 영향을 받지 않았고, 수영스트레스(SS)로 나타나는 혈장 corticosterone(CS)의 증가가 propylthiouracil 전처치 (PTU) 및 1-thyroxine 전처치 (T4)로 각각 다소의 감소 및 증강됨을 보였으나, SS에 의한 혈장 CS증가에 대한 clonidine의 억제작용은 PTU 및 T4의 영향을 받지 않았다. SS부하로 뇌 3-methoxy-4-hydroxyphenylglycol 함량(MHPG)가 유의하게 증가되고 clonidine에 의하여는 MHPG가 현저히 감소되었으나 뇌 norepinephrine 함량(NE)은 별 변동을 보이지 않아서 MHPG/NE비는 SS와 clonidine에 의하여 각각 현저한 증가 및 감소를 나타내었다. 아울러, PTU및 T4은 각각 뇌NE을 유의하게 감소 또는 증가시켰으나 뇌 MHPG에는 별 영향을 미치지 않았다. Clonidine은 SS에 의한 뇌 MHPG 및 MHPG/NE비의 증가를 모두 현저히 억제하였으며 그 억제작용은 PTU 및 T4에 의하여 별 영향을 받지 않았다. 이상의 성적으로 미루어서, 마우스의 일과성 자발운동양상 및 스트레스반응으로 나타나는 혈장 corticosterone의 증가현상등이 갑상선-홀몬의 변동에 별 영향을 받지 않으며, 시상하부-뇌하수체-부신계의 활성화가 시상하부의 norepinephrine성 신경-흥분에 매게되어 나타나는 바, 스트레스성 혈장 corticosterone 증가에 대한 clonidine의 억제작용이 그의 절전-${\alpha}_2-adrenoceptor\;agonist$ 작용에 기인되는 것으로 사료된다. The circadian rhythm of spontaneous motor activity was not significantly altered by $T_4$(4mg/kg, i.p. inj. once a day for 5 days: $T_4$) and PTU (fed ad lib in 0.01% drinking water for 5 weeks: PTU). The plasma thyroxine level was markedly increased by $T_4$ but reduced by PTU, and the plasma thyrotropin level was markedly increased by PTU but moderately increased by $T_4$. Clonidine slightly increased the plasma CS level, but the clonidine effect was significantly enhanced by $T_4-pretreatment$. The brain NE and MHPG contents were little affected by $T_4$ but the NE content was significantly decreased by PTU. The SS-induced increase of plasma CS level was moderately decreased by PTU but increased by $T_4$. However, clonidine significantly inhibited the SS-induced increase, and the inhibitory effect of clonidine was not significantly affected by PTU and $T_4$, respectively. The brain MHPG content and MHPG/NE ratio were significantly decreased by clonidine but increased by SS. The clonidine- and SS-induced changes of brain MHPG content and MHPG/NE ratio were not altered by $T_4$. PTU did not affect the SS-induced increase of brain NE turnover but significantly attenuated the clonidine-induced decrease. The SS-induced increases of brain MHPG content and MHPG/NE rtatio were markedly inhibited by clonidine, and the inhibitory effect of clonidine was not affected by $T_4$ and PTU, respectively. These results suggest that the responses to swim-stress is not signigicantly affected by the alteration of thyroid function and that the hypothalamo-adenohypophysis-adrenocortical stimulation in response to swim-stress seems to be mediated via hypothalamic noradrenergic activation, and the stress response may be inhibited by the agonistic activity of clonidine on the presynaptic ${\alpha}_2-adrenoceptor$.

The activation of α₂-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

Sung-Su Kim,Soo-Hyun Park,Jae-Ryung Lee,Jun-Sub Jung,Hong-Won Suh 대한생리학회-대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.5

The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 µg/27 µl) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 µg/5 µl) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factorα (TNF-α) induced by sepsis. Clonidine administered i.t. or i.p. increased p-AMPKα1 and p-AMPKα2, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of p-AMPKα1 and p-AMPKα2, or down-regulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality.

Orignal Paper : Inhibitory effect of clonidine on kainic acid-induced seizure activity in regularly exercised mice

박석 ( Sok Park ),김희재 ( Hee Jae Kim ),김정석 ( Jung Suk Kim ),유영준 ( Young June Yoo ),이진 ( Jin Lee ) 한국운동영양학회 2011 Physical Activity and Nutrition (Phys Act Nutr) Vol.15 No.2

Regular exercise and clonidine have been shown to affect epilepsy. After 6 weeks of training involving swimming, the total body weight of trained mice was significantly lower than that of sedentary mice. Further, the blood lactate concentrations of these mice were statistically more stable than those of sedentary mice. These results indicate that the training program increased aerobic resistance in mice. Systemic kainic acid (KA) injection (30 mg/kg) evoked seizure activity in mice within 10 min. Further, clonidine (α2-adrenoreceptor agonist, 4 mg/kg) was injected 30 min before KA. Both the clonidine-treated group and exercised group experienced decreased seizure activity 10 min after KA injection and maintained seizure activity rating scores of 3-3.5 for 2 h afterwards. To examine whether or not clonidine and exercise had synergistic effects, we exercised animals and then treated with clonidine 30 min before KA administration. The clonidine and exercise group experienced decreases in seizure activity by 2 rating scores, and the regimen did not lead to death. Further, the clonidine and exercise group experienced decreased rates of mortality as well as motor impairment. These results suggest that the combination of regular exercise and therapy with an anticonvulsant agent such as clonidine could be a more efficient method for the prevention and/or treatment of epilepsy than exercise alone.

Comparison of Clonidine and Midazolam Premedication Before Endoscopic Sinus Surgery: Results of Clinical Trial

Katarzyna Wawrzyniak,Krzysztof Kusza,Jacek B. Cywinski 대한이비인후과학회 2014 Clinical and Experimental Otorhinolaryngology Vol.7 No.4

Objectives. Premedication with clonidine has been found to reduce the bleeding during endoscopic sinus surgery (ESS), therefore lowering the risk of surgical complications. Premedication is an essential part of pre-surgical care and can potentially affect magnitude of systemic stress response to a surgical procedure. The aim of this study was to compare the efficacy of premedication with clonidine and midazolam in patients undergoing sinus surgery. Methods. Forty-four patients undergoing ESS for chronic sinusitis and polyp removal were enrolled and randomly assigned to receive either oral clonidine or midazolam as a premedication before receiving propofol/remifentanil total intrave- nous anesthesia. The effect of this premedication choice on anesthetic requirements, intraoperative hemodynamic profile, preoperative anxiety and sedation as well as postoperative pain and shivering were examined in each pre- medication group. Results. Total intraoperative remifentanil requirement was lower in the clonidine group as compared to the midazolam group 503.2±147.0 µg vs. 784.5±283.8 µg, respectively (P<0.001). There was no difference between groups in re- quired induction dose of propofol, level of preoperative anxiety, level of sedation and postoperative shivering. Intra- operative systemic blood pressure and heart rate response had a more favorable profile in patients premedicated with clonidine. Postoperative pain assessed by visual analogue scale for pain was lower in the clonidine group compared with to the midazolam premedication group. Conclusion. Premedication with clonidine provides better attenuation of hemodynamic response and reduction of intraop- erative remifentanil requirements in patients undergoing ESS. Postoperative pain seems to be better controlled after clonidine premedication as well.