• Archives of Pharmacal Research
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• 제14권2호
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• pp.181-187
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• 1991

The muscarinic antagonist 1-[benzilic 4, 4'-$[^3H]$ QUINUCLIDINYL BENZILATE $([^3H]$ QNB) bound to a single class of muscarinic receptors with high affinity in rabbit ileal membranes. The $K_D\;and\;B_{ max}$ values for $([^3H]$ QNB calculated from analysis of saturation isotherms were 52.5 pM AND 154 fmol/mg, respectively. Chlopheniramine (CHP), histamine $H_1$ blocker, increased $K_D$ vlue for $([^3H]$QNB without affecting the binding site concentrations and Hill coefficient. The $K_i$ value of CHP for inhibition of $([^3H]$QNB binding in ileal membranes was 1.44\mu{M}$ and the pseudo-Hill coefficient for CHP was close to unit. In the functional assay carbachol, muscarinic agonist, increased the contractile force of ileum with $ED_{50}$ value of $0.11\mu{M}$. CHP caused the rightward shift of the dose-response curve to carbachol. The $pA_2$ value of CHP determined from Schild analysis of carbacholinduced contraction was 5.77 and the slope was unity indicating competitive antagonism with carbachol. The dissociation constant $(K_i)$ of CHP obtained in competitive experiments with $([^3H]$ QNB was similar to the $K_A$ value (1.69 \mu{M)}$ of CHP as inhibitor of carbachol induced contraction in rabbit ileum. This result suggest that the binding of $H_i$ blocker. CHP, vs $([^3H]$QNB to muscarinic receptors in ileal membranes represents an interaction with a receptor of physiological relevance.

• Journal of Yeungnam Medical Science
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• 제17권1호
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• pp.12-20
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• 2000

The memory of pain can be more damaging than its initial experience. Several factors arc related the directions of pain memory: current pain intensity, emotion, expectation of pain, and peak intensity of previous pain. The possible mechanisms behind the memory of pain are neuroplastic changes of nervous system via peripheral and central sensitization. Peripheral sensitization is induced by neurohumoral alterations at the site of injury and nearby. Biochemicals such as K+, prostaglandins, bradykinin, substance P, histamine and serotonin, increase transduction and produce continuous nociceptive input. Central sensitization takes place within the dorsal horn of spinal cord and amplifies the nociceptive input from the periphery. The mechanisms of central sensitization involve a variety of transmitters and postsynaptic mechanisms resulting from the activations of NMDA receptors by glutamate. and activation of NK-1 tachykinnin receptors by substance-P and neurokinnin. The clinical result of peripheral and central sensitization is hyperalgesia, allodynia, spontaneous pain, referred pain, or sympathetically maintained pain. These persistent sensory responses to noxious stimuli arc a form of memory. The hypothesis of preemptive analgesia is that analgesia administered before the painful stimulus will prevent or reduce subsequent pain and analgesic requirements in comparison to the identical analgesic intervention administered after the painful stimulus, by preventing or reducing the memory of pain in the nervous system. Conventionally, pain management was initiated following noxious stimuli such as surgery. More recently, however many have endorsed preemptive analgesia initiated before surgery. Treatments to control postsurgical pain are often best started before injury activates peripheral nociceptors and triggers central sensitization. Such preemption is not achieved solely by regional anesthesia and drug therapy but also requires behavioral interventions to decrease anxiety or stress. Although the benefit of preemptive analgesia may not be obvious in every circumstance, and in many cases may not sufficient to abolish central sensitization, it is an appropriate and human goal of clinical practice.

• 한국패류학회지
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• 제25권1호
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• pp.15-22
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• 2009

Because it is known that bivalve hearts contain various modulatory systems activated by neuroendocrine substances, it was examined whether different classes of endogenous and synthetic drugs of neuroendocrinological importance can influence cardiac functions of the Pacific oyster Crassostrea gigas. Cholinergically active agents acetylcholine and carbachol increased heart rates while diminishing cardiac contractility. Adrenergically active substances norepinephrine (NE) and epinephrine (Epi) also induced heart rate increase and contractility decrease. An $\alpha_1$-adrenergic receptor-selective agonist phenyephrine (PE) failed to modulate either parameter. The Epi-induced heart rate increase and contractile depression were both blocked significantly by non-selective $\beta_1/\beta_2$-adrenergic antagonist propranolol. A $\beta_1$-selective antagonist atenolol prevented Epi-induced heart rate decrease but not the contractile depression, suggesting possible $\beta_2$ receptors for Epi-induced contractile depression. The three autacoids examined exerted discrete responses: histamine increased heart rate and depressed contraction; $\gamma$-amino-butyric acid increased both parameters; serotonin failed to change either parameter. The 5 piscine anesthetic agents examined, MS-222, benzocaine, quinaldine, urethane, pantocaine and pentobarbital, all failed to influence the cardiac function of oysters. Collectively, activities of neuroendocrinologically acting agents in mammals showed unexpected and distinct activities from those in mammalian cardiovascular systems. These results obtained from substances of different physiological functions can serve as a basis for understanding neuroendocrine control of the heart function in Pacific oyster.

• 대한기관식도과학회지
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• 제4권1호
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• pp.64-72
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• 1998

This study aimed at observing the effect of diazepam on the contractility of trachealis muscle isolated from canine trachea, possible involvement of central or peripheral type benzodiazepine receptor, and the calcium related mechanism of action of diazepam. Trachealis muscle strips of 15 mm long were suspended in an isolated organ bath containing 1 ml of physiologic salt solution maintained at $37^{\circ}C$, and aerated with 95% $O_2$ /5% $CO_2$. Isometric myography was performed. Diazepam reduced the basal tone concentration dependently, and this inhibitory action was not affected by neither flumazenil, a central benzodiazepine receptor antagonist, nor PK11195, a peripheral benzodiazepine receptor antagonist. Pretreatment with diazepam showed the inhibitory effect on the concentration-response curves to agonists such as bethanechol, 5-hydroxytryptamine and histamine. Diazepam also caused concentration-related inhibition of contraction with potassium chloride 30 mM. The effect of diazepam on the basal tone and potassium chloride-induced contraction with calcium channel blockers were compared. Similar results were obtained in canine trachealis with verapamil, nifedipine and diltiazem. These results suggest that diazepam relax an airway muscle not via specific receptors but by a similar action as calcium channel blockers in canine trachealis muscle.

• 대한의사협회지
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• 제61권11호
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• pp.670-677
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• 2018

Many of the patients visit the doctors because of itching sensation. Itching is an unpleasant sensation. In the epidermal keratinocytes, various neurotransmitters and receptors are related itching. The itch signal is mainly transmitted through the lateral spinal ganglion-derived nerve fibers extending to the lower epidermis. Many mediators such as histamine are involved in the itching pathway. It can be helpful in the treatment of patients having itching sensation with a lot of new therapies from the basic medication such as antihistamines. Also, many drugs are currently under study.

• 한국어병학회지
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• 제14권1호
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• pp.31-36
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• 2001

해수에 적응된 뱀장어, Anguilla japonica의 장 세포막으로부터 새로운 clonidine의 결합부위가 있음이 밝혀졌다. Clonidine의 특이적인 결합부위는 적어도 2개의 부위 (high affinity $K_d=1.4{\pm}0.3$ nMn= 5, low affinity $K_d=175{\pm}34$ nM)를 가지고 있었다. 2nM [$^3H$]clonidine의 특이적인 결합은 $20^{\circ}C$, pH 7.5에서 최적 결합능을 가지고 있었고, 라벨되지 않은 clonidine에 의해 가역적인 반응을 보였다. 이러한 결합은 adrenaline, yohimbine과 rauwolscine에 의한 저해능은 약하였다. 그리고 대부분의 결합부위는 $\alpha_2$-adrenoceptor와는 상이하였다. Clonidine의 특이적인 결합은 다양한 imidazoline/guanidinium약물에 의해 억제되었다. Competition 실험의 결과, 2nM[$^3H$]clonidine의 치환 rank order는 다음과 같다. guanabenz > cirazoline = naphazoline=UK14,304= ST587 $\geq$ clonidine $\geq$ idazoxan = RX821002 = tolazoline > ST93 = oxymetazoline = amiloride = ST91 > yohimbine = efaroxan = rauwolscine $\geq$ adrenaline = ST567 = histamine = agmatine. 이러한 순서는 포유류에 분류된 imidazoline receptorl($I_1$), imidazoline receptor 2($I_2$) 및 imidazoline/guanidinium receptive sites(IGRS)형태와는 틀리기 때문에 새로운 imidazoline receptor라고 생각된다. 지금까지 보고된 포유류의 세포와 조직에서 IGRS의 생리학적인 역할은 명확하지 않지만, 해수뱀장어 장은 IGRS의 세포에 있어서의 역할 그리고 IGRS의 내인성(內因性) ligand가 무엇인가에 대한 좋은 모델이 될 수 있다고 생각되어진다.

• 대한약리학회지
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• 제31권2호
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• pp.219-231
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• 1995

Vasoactive intestinal polypeptide(VIP) and ${\beta}-adrenergic$ agonists have immunomodultory effects on the peripheral blood T-lymphocytes of rat through their own receptors. Both of them utilize the same signal transduction pathway. That is, the stimulatory guanine nucleotide binding protein(G protein) mediates the receptor-adenylyl cyclase coupling, producing intracellular increase of cyclic adenosine monophosphate(cAMP). In the previous experiment, propranolol, a ${\beta}-adrenergic$ receptor blocker, inhibited the VIP-induced protein phosphorylation in lymphocytes. However, propranolol could not block the effect induced by forskolin. Therefore, this study was designed to elucidate the mechanism of the inhibitory action of propranolol on the effects of VIP. Using peripheral blood lymphocytes of rats, the effect of propranolol on the receptor binding characteristics of VIP was observed. And the effects of propranolol were compared to the effects of timolol on the cAMP increase induced by isoproterenol, VIP or forskolin. The results obtained are as follows. 1) Receptor binding study showed no significant differences in the affinity or density of VIP receptor between the control and propranolol-pretreated groups. 2) VIP-induced increase of cAMP was inhibited by propranolol, but not by timolol. 3) Both propranolol and timolol suppressed the isoproterenol-induced cAMP increase. 4) Propranolol also inhibited the histamine-induced cAMP increase. 5) Propranolol did not inhibit the increase of cAMP stimulated by forskolin. 6) Lidocaine did not block the VIP-induced cAMP increase. These results show that the inhibitory mechanism of propranolol is not related to ${\beta}-adrenergic$ receptor or its membrane stabilizing effect, and it is suggested that propranolol can block the effects of VIP by inhibiting the intermediate step between the VIP receptor and adenylyl cyclase.

• The Korean Journal of Physiology and Pharmacology
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• 제24권4호
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• pp.329-338
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• 2020

Rhinorrhea in allergic rhinitis (AR) is characterized by the secretion of electrolytes in the nasal discharge. The secretion of Cl^- and HCO₃^- is mainly regulated by cystic fibrosis transmembrane conductance regulator (CFTR) or via the calcium-activated Cl^- channel anoctamin-1 (ANO1) in nasal gland serous cells. Interleukin-4 (IL-4), which is crucial in the development of allergic inflammation, increases the expression and activity of ANO1 by stimulating histamine receptors. In this study, we investigated ANO1 as a potential therapeutic target for rhinorrhea in AR using an ANO1 inhibitor derived from a natural herb. Ethanolic extracts (30%) of Spirodela polyrhiza (SP_EtOH) and its five major flavonoids constituents were prepared. To elucidate whether the activity of human ANO1 (hANO1) was modulated by SP_EtOH and its chemical constituents, a patch clamp experiment was performed in hANO1-HEK293T cells. Luteolin, one of the major chemical constituents in SP_EtOH, significantly inhibited hANO1 activity in hANO1-HEK293T cells. Further, SP_EtOH and luteolin specifically inhibited the calcium-activated chloride current, but not CFTR current in human airway epithelial Calu-3 cells. Calu-3 cells were cultured to confluency on transwell inserts in the presence of IL-4 to measure the electrolyte transport by Ussing chamber. Luteolin also significantly inhibited the ATP-induced increase in electrolyte transport, which was increased in IL-4 sensitized Calu-3 cells. Our findings indicate that SP_EtOH and luteolin may be suitable candidates for the prevention and treatment of allergic rhinitis. SP_EtOH^- and luteolin-mediated ANO1 regulation provides a basis for the development of novel approaches for the treatment of allergic rhinitis-induced rhinorrhea.

• 대한약리학회지
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• 제24권1호
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• pp.93-101
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• 1988

돼지 우관상동백을 적출하여 항경련제인 oxybutynin의 약리작용을 조사하였다. 1. Acetylcholine (ACh)과 KCl은 관상동맥을 수축시켰고 이 수축효과는 용량의존적이었다. ACh의 수축효과는 내피손상표본 $(EC_{50}=0.52\;{\mu}M)$에서 내피표본 $(EC_{50}=0.52\;{\mu}M)$보다 약 2배 강화되있으나 KCl의 수축효과는 양군간에 차이가 없었다. 2. $ACh(1.0\;{\mu}M)$의 수축효과는 oxybutynin과 atropine에 의 하여 용량의존적으로 억제되었고 두 약물의 $(IC_{50}$는 각각 11.0 nM과 0.47 nM로 atropine이 약 23배나 더 예민하였다. 그러나 KCl (35 mM)의 수축효과는 atropine으로는 전혀 영향받지 않았고 oxybutynin으로는 용량의존적으로 억제 되었으며 $(IC_{50}=49.7\;{\mu}M)$이였다. 3. ACh의 용량반응곡선은 oxybutynin $(IC_{50}=11\;nM)$ 및 atropine $(IC_{50}=0.47\;nM)$ 전처 리 하에서 우측으로 평 행 이 동되 있고, KCI의 용량반응곡선은 oxybutynin $(IC_{50}=49.7\;nM)$ 전처리하에서 우측으로 비상경적 이동을 일으켰다. 4. Oxybutynin은 Bay K 8644 $(0.1\;{\mu}M)$의 수축효과를 용량의존적 으로 억제하였고 $(IC_{50}=63.0\;{\mu}M)$이었으며 , histamine $(35\;{\mu}M)$의 수축효과는 oxybutynin의 최대량 $(500\;{\mu}M)$으로 부분억제 (최대 50%)만을 일으켰다. 이상의 성적으로 적출돼지 관상동백에서 내피세포는 ACh에 의한 수축반응에 억제적 영향을 미치며, oxybutynin은 강력한 muscarine receptor 차단작용과 calcium influx 억제작용에 의하여 혈관근 이완을 일으킨다고 추론하였다.

• 대한약리학회지
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• 제24권2호
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• pp.203-216
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• 1988

돼지, 가표 및 가토의 뇌동맥에서 기저동맥 (basilar artery, BA)과 circle of willis동맥 (WC)의 동맥환을 만들어 혈관수축제와 calcium 길항제의 효과 그리고 내피세포의 역할은 검토하였다. 돼지 BA와 WC에 서 norepinephrine (NE), phenylephrine (PE)및 epinephrine (EP)은 propranolol $10^{-6}M$ 전처리하에서 그리고 KCI, histamine, 5-hydroxytryptamine (5-HT) 및 angiotensin은 모두 용량의존성 수축반응을 일으켰다. 그 최대수축력은 angiotensin에서 가장 적었고, 5-HT에서 가장 강력하였다. KCI 35 mM수축반응은 calcium 길항제로 용량의존성으로 억제되었고, 그 효력은 nifedipine > > diltiazem > flunarizine > oxybutynin > isosorbide dinitrate (ISDN) > glycerl trinitrate의 순서였다. 5-HT $10^{-5}M$의 수축반응은 nifedipine으로는 용량의존성으로 억제 되었으나 diltiazem과 ISDN으로는 경미한 억제만을 일으켰다. 내피세포동맥환에서 KCI 35 mM의 수축반응은 acetylcholine (ACh)으로 거의 영향받지 않았으나 $PGF_{2{\alpha}}\;10^{-5}M$의 수축반응은 ACh과 adenosine으로 용량의존성으로 억제되었고, 이 내피세포 의존성억제는 nifedipine $10^{-6}M$로는 영향받지 않으나 methylene blue $50\;{\mu}M$로는 현저히 억제되었다. 네피제거동맥환에의 $PGF_{2{\alpha}}$의 수축반응은 ACh의 영향이 없거나 더욱 수축되었다. 내피세포를 제거하지 않은 가토흉부대동맥편을 bath에 함께 넣어주면 ACh의 용량의존성 이완반응이 나타났고 이 이완반응도methylene blue로 억제되었다. 가묘 BA와 WC에서 5-HT와 NE는 용량의존성 수축반응을 일으켰고 ACh도 내피세포 존재유무와 관계없이 강력한 용량의존성 수축반응을 일으켰으며 그 최대수축력은 ACh에서 가장 강력하였다. 내피세포동맥환에서 5-HT $10^{-5}M$의 수축반응은 ACh에 의하여 이완반응없이 더욱 수측되었다. 가토 BA에서 5-HT와 NE는 응량의존성 수축반응을 일으졌고5-HT의 수축반응이 더욱 현저하였다. 내피세포동맥환에서 5-HT $10^{-5}M$의 수축반응은 ACh $10^{-5}M$로 현저하게 이완되있고 이 내피세포의존성 이완반응은 atropine $10^{-7}M$로는 억제되었으나 diltiazem $10^{-6}M$로는 거의 억제되지 않았다. 이상의 실험성적은 돼지와 가토의 뇌동맥에서 ACh은 내피세포-의존성 이완반응을 일으키며그 이완반응은 muscarinic receptor를 통해 나타났고, 가묘뇌동맥에서 ACh은 혈관수축제의 역할을 갖고 있음을 시사하고 있다.