• Biomolecules & Therapeutics
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• v.8 no.2
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• pp.125-131
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• 2000

Idazoxan, $\alpha$$_2$-adrenergic antagonist, produced antidiuretic action by administration into the vein and diuretic action only in ipsilateral kidney by injection into a renal artery in dog. These studies were performed for investigation of mechanism on the renal action induced by idazoxan. Antiduretic action by idazoxan given into vein and diuretic action only in ipsilateral kidney by idazoxan injected into a renal artery were blocked entirely by renal denervation. Antidiuretic action of idazoxan given into the vein was weakened by UK 14,304, $\alpha$$_2$-adrenergic agonist, pretreated into the vein. Above results suggest that antidiuretic action of idazoxan given into the vein is caused by blocking of $\alpha$$_2$-adrenergic receptor, diuretic action only in ipsilateral kidney of idazoxan injected into a renal artery by blocking of $\alpha$$_2$-adrenergic receptor in the kidney.

• Biomolecules & Therapeutics
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• v.8 no.2
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• pp.132-139
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• 2000

This study was performed far investigation of influence on renal function of idazoxan, $\alpha_{2}$-adrenergic antagonist, using the dog. Idazoxan, when giver. into vein, produced the decrease of urine volume(vol) accompanied with the reduction of free water clearance($C_{H2O}$), amounts of sodium excreted in urine($E_{Na}$), with the increase of potassium excreted in urine($E_{K}$), and so ratios of potassium against sodium($K^{+}/Na^{+}$) were elevated, at this time, greatened reabsorption rate of sodium and diministered that of potassium in renal tubules were appeared. Idazoxan administered into a renal artery elicited the augmentation of vol, glomerular filtration rate(GFR), renal plasma flow(RPF) and no change of filtration fraction(FF) in only ipsilateral kidney, whereas $E_{Na},\;E_{K}\;and\;K^{+}/Na^{+}$ were increased and $C_{H2O}$ was decreased in both control and experimental kidney. Idazoxan given into carotid artery showed partial increased vol, remarkable expanded RPF and unchanged GFR, and so filtration fraction(FF) was markedly reduced. Above results suggest that anti- diuretic action of idazoxan given into vein is mediated by reduction of $C_{H2O}\;and\;E_{Na}$, diuretic action only in the ipsilateral kidney by idazoxan given into a renal artery is caused by hemodynamic improvement through expansion of vas afferens in glomeruli.

• The Korean Journal of Pain
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• v.9 no.2
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• pp.318-325
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• 1996

Background: Sympathectomy relieves pain in sympathectically maintained pain, and subcutaneous injection of norepinephrine(NE) can rekindle mechanical allodynia. However, the mechanism of rekindling is not clear. The purpose of this study is to investigate which subtype of $\alpha$-adrenoceptor is involved in NE-induced rekindling of mechanical allodynia in sympathectomized neuropathic rats. Methods: Neuropathic injury was produced by tightly ligating the left L5 and L6 spinal nerves of 36 male Sprague-Dawley rats and bilateral lumbar sympathectomy was done at two weeks postoperatively. Starting at 7 days after sympathectomy, rekindling of mechanical allodynia was induced by NE and clonidine injected into the left paw, which was reversed by pretreatment of phentolamine and idazoxan. Mechanical allocynia was quantified by measuring the frequency of foot lifts to two von Frey filaments applied to the paw. Results: All tested rats displayed well-developed signs of mechanical allodynia at the left paw that were abolished by a bilateral lumbar sympathectomy. Subcutaneous (s.c.) injection of NE (0.05 ${\mu}g$) into the affected paw of sympathectomized neuropathic rats rekindled previous mechanical allodynia. These effects could be mimicked by an ${\alpha}_2$-receptor agonist clonidine, but not by an ${\alpha}_1$-receptor agonist phenylephrine. The NE-induced rekindling of mechanical allodynia was significantly reduced by prior s.c. injection of a mixed $\alpha$-receptor antagonist phentolamine (20${\mu}g$) and ${\alpha}_2$-receptor antagonist idazoxan(20${\mu}g$), but not by a ${\alpha}_1$-receptor antagonist terazosin (20${\mu}g$). The pretreatment of idazoxan produced dose-related inhibition of NE-induced rekindling of mechanical allodynia. The rekindling induced by ${\alpha}_2$-receptor agonist clonidine (5${\mu}g$) was also reversed by prior s.c. injection of ${\alpha}_2$-receptor antagonist idazoxan (20${\mu}g$). Conclusion: Subcutaneous injection of NE into the paw of sympathectomized neuropathic rats rekindles mechanical allodynia, which is reversed by an ${\alpha}_2$-, but not by an ${\alpha}_1$-receptor antagonist. Therefore, rekindling of mechanical allodynia in sympathectomized neuropathic rats is mediated by ${\alpha}_2$-adrenoceptor.

• The Korean Journal of Pharmacology
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• v.22 no.1 s.38
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• pp.45-50
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• 1986

The involvement of central $_{{\alpha}2}$-adrenoceptors in the development of muricide (mouse-killing behavior) in the olfactoly bulbectomized (OB) rats was strudied. The fractional turnover rate of noradrenaline (NA) in forebrain from OB muricidal rats was significantly lowered than that from sham rats. However, after yohimbine or idazoxan treatment, NA turnover was significantly increased in concert with inhibition of the development of muricide in OB rats. By radioligand binding studies with $[^3H]$ yohimbine, the maximum binding $(B_{max})$ of $[^3H]$ yohimbine to cerebral cortical membrane from OB rats was significantly higher than that from sham rats without change of affinity for agonists and antagonists$(K_i)$. With these results it was suggested that muricidal behavior of OB rats has a close relevance to the hyperactivity of central $_{{\alpha}2}$-adrenoceptor system.

• Journal of Korean Physical Therapy Science
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• v.9 no.2
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• pp.111-122
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• 2002

In oriental medicine, manual-acupuncture and electroacupuncture (EA) have been widely utilized to cure several inflammatory diseases such as arthritis. We designed this experiment to find neurochemical mechanism related to electroacupuncture induced anti-inflammatory effect on mouse air pouch model. EA with both low frequency (1 Hz) and high frequency (120 Hz) was treated after induction of inflammation in air pouch using injection of zymosan. To verify the role of opioid system in electroacupuncture-induced anti-inflammatory effect, naloxone (10 mg/kg) was pretreated. In addition, idazoxan (5 mg/kg) was pre-treated to evaluate the possible effect of endogenous adrenergic system in autonomic system on EA induced anti-inflammatory effect. As results of this study, naloxone pretreatment did not change the anti-inflammatory effect evoked by high frequency EA, while low frequency EA(1 Hz) induced anti-inflammatory effect was dramatically suppressed by naloxone pretreatment. These data indicated that endogenous opioid system might be extensively involve in anti-inflammatory effect evoked by not high frequency, but low frequency EA. However, idazoxan pretreatment did not produce any modulatory effect on both low and high frequency EA induced anti-inflammatory effect, suggesting that EA induced anti-inflammatory effect was not mediated by endogenous adrenergic system. In conclusion, these data strongly suggested that EA induced anti-inflammatory effect is mediated by endogenous opioid system, not endogenous adrenergic system.

• Journal of fish pathology
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• v.14 no.1
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• pp.31-36
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• 2001

A novel clonidine binding sites were characterized in the intestinal membrane isolated from seawater eels, Anguilla japonica. The specific clonidine binding sites consisted of at least two classes, high affinity ($K_d=1.4{\pm}0.3$ nM n = 5) and low affinity ($K_d=175{\pm}34$ nM n = 5) sites. The specific binding of 2 nM [$^3H$]clonidine was most enhanced at $20^{\circ}C$ and pH 7.5, and reversed by unlabelled clonidine. Such binding was hardly inhibited by adrenaline, yohimbine or rauwolscine, indicating that most binding sites are distinct from $\alpha_2$-adrenoceptor. The specific clonidine binding sites was inhibited by various imidazoline/guanidinium drugs, indicating existence of imidazoline/guanidinium receptive sites (IGRS) or imidazoline receptors in the eel intestine. Competition experiments revealed that rank order to displace 2 nM [$^3H$]clonidine from their binding sites was as follows : guanabenz > cirazoline = naphazoline = UK14,304 = ST587 $\geq$ clonidine $\geq$ idazoxan = RX821002 = tolazoline > ST93 = oxymetazoline = amiloride = ST91 > yohimbine = efaroxan = rauwolscine $\geq$ adrenaline = ST567 = histamine = agmatine. Although physiological role of IGRS is not clear yet even in mammalian cell/tissues, eel intestine may be a good model to elucidate how the IGRS act in the cell and to decide what is the endogenous ligand for the IGRS.

• The Korean Journal of Pharmacology
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• v.21 no.2
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• pp.90-98
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• 1985

1) In the study of the forced-swimming test in mice (FSM), the duration of immobility posture was dose-dependently shortened by ${\alpha}_2$-agonists, clonidine and guanabenz. BH-T 933 and oxymetazoline also decreased it . Xylazine rather increased the immobility duration at low dose. 2) ${\alpha}_1$-Agonists, cirazoline, amidephrine and methoxamine, however, showed inconsistent effect on the immobility duration (ID). 3) The decrease in ID by clonidine and guanabenz was antagonized by pretreatment with yohimbine, idazoxan and phentolamine (${\alpha}_2$antagonist), but not by prazosin and corynanthine (${\alpha}_1$-antagonist) .4) The ID in the FSM was shortened dose-dependently by d-amphetamine, and it was also antagonized by yohimbine, but not by prazosin. 5) In the mice pretreated with either ${\alpha}$-methyl-p-tyrosine or reserpine, or with combination of both, the decrease in ID was still evoked by clonidine. 6) When the mice were chronically treated with antidepressants (desipramine and imipramine), or with electroconvulsive shock, clonidine still decreased the ID as it did in the control. 7) These results provided the evidences to hypothesize that the change of the ID in the FSM is closely related with the postsynaptie ${\alpha}_2$-adrenoceptor located on the central noradrenergic neuron body. Furthermore, it is assumed that this escape-directed behavior enhanced by ${\alpha}_2$-adrenoceptor agonist may be the result in some analogy with the incentive of drives which are directed toward the self-preservation.

• Korean Journal of Veterinary Research
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• v.37 no.2
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• pp.331-338
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• 1997

최근 동물의 진통 및 진정을 목적으로 널리 사용되고 있는 imidazole 유도체인 clonidine, medetomidine, etomidate 등의 약물과 xylazine의 효과를 발정정지기의 척출 돼지 자궁근에서 검토하였다. Clonidine($10^{-8}{\sim}10^{-6}M$)이나 medetomidine($10^{-8}{\sim}10^{-6}M$)은 xylazine과 비슷한 정도로 용량의존적인 자궁근의 수축을 일으켰다. Clonidine, medetomidine, xylazine 등의 $EC_{50}$는 각각 24.7nM, 19.9nM, 45.1nM이었다. 그러나 etomidate는 $10^{-6}M$ 미만의 농도에서 반응이 거의 없었으며, $10^{-6}M$ 이상에서 수축반응을 일으켰다. 이들 agonists의 효과는 yohimbine($10^{-8}{\sim}10^{-6}M$), idazoxan($10^{-7}{\sim}10^{-5}M$), tolazoline($10^{-7}{\sim}10^{-5}M$) 등의 ${\alpha}_2-adrenoceptor$ antagonists에 의해서 차단되었으나, ${\alpha}_1-adrenoceptor$ antagonist인 prazosin ($10^{-6}M$)에 의해서는 차단되지 않았다. 또한 $Ca^{2+}-free$ medium이나 verapamil($10^{-5}M$)의 전처치에 의해서 이들 agonist의 효과가 완전히 차단되었다. 결론적으로 발정정지기의 돼지 자궁근에서 clonidine, medetomidine, etomidate, xylazine 등은 ${\alpha}_2-adrenoceptors$의 흥분을 통해 자궁근의 수축을 일으키며, 이 효과는 voltage-dependent $Ca^{2+}$ channels을 통한 extracellular $Ca^{2+}$ influx의 증가에 의한 것으로 추론하였다.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.6
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• pp.657-666
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• 2017

Paclitaxel, a chemotherapeutic drug, induces severe peripheral neuropathy. Gabapentin (GBT) is a first line agent used to treat neuropathic pain, and its effect is mediated by spinal noradrenergic and muscarinic cholinergic receptors. Electro-acupuncture (EA) is used for treating various types of pain via its action through spinal opioidergic and noradrenergic receptors. Here, we investigated whether combined treatment of these two agents could exert a synergistic effect on paclitaxel-induced cold and mechanical allodynia, which were assessed by the acetone drop test and von Frey filament assay, respectively. Significant signs of allodynia were observed after four paclitaxel injections (a cumulative dose of 8 mg/kg, i.p.). GBT (3, 30, and 100 mg/kg, i.p.) or EA (ST36, Zusanli) alone produced dose-dependent anti-allodynic effects. The medium and highest doses of GBT (30 and 100 mg/kg) provided a strong analgesic effect, but they induced motor dysfunction in Rota-rod tests. On the contrary, the lowest dose of GBT (3 mg/kg) did not induce motor weakness, but it provided a brief analgesic effect. The combination of the lowest dose of GBT and EA resulted in a greater and longer effect, without inducing motor dysfunction. This effect on mechanical allodynia was blocked by spinal opioidergic (naloxone, $20{\mu}g$), or noradrenergic (idazoxan, $10{\mu}g$) receptor antagonist, whereas on cold allodynia, only opioidergic receptor antagonist blocked the effect. In conclusion, the combination of the lowest dose of GBT and EA has a robust and enduring analgesic action against paclitaxel-induced neuropathic pain, and it should be considered as an alternative treatment method.