• 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.

• 대한약리학회지
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• 제29권1호
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• pp.9-22
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• 1993

허혈성 뇌손상시 칼슘길항제, 항산화제와 산소라디칼 제거제 그리고 흥분성 아미노산 수용체 길항제의 보호효과를 검토하기 위해 본 연구에서는 랫트 뇌 해마조직 절편을 산소와 포도당을 제거한 반응액에 노출시켜 실험적 허혈상태를 유도하였다. 그리고 여러 약물을 처리한 상태에서 허혈시의 뇌세포 손상정도를 생화학적 지표들(절편내 ATP와 반응액내 lactate 및 malondialdehyde (MDA)유리량)을 측정하여 검토하였다. 60분까지 허혈상태를 유발시킨 경우 시간에 따라 절편내 ATP 함량이 감소하였고 lactate 유리량이 증가하였다. 그 후 산소와 포도당이 든 반응액으로 바꿔주니 이들 생화학적 변화들이 회복되는 양상을 보였다. 그러나 본 실험조건에서 허혈상태로부터 완전히 회복되지는 않았다. 동일한 허혈조건에서 verapamil과 비타민 E는 ATP 함량 감소와 절편으로부터의 lactate 유리량의 증가에 대해 보고효과를 보였다. 그리고 verapamil과 diltiazem은 반응액내로의 MDA유리를 감소시켰다. Superoxide dismutase (SOD), glutathione과 MK-801 (NMDA 수용체 길항제)은 20분 허혈조건에서 ATP 함량을 증가시켰으나 그외 다른 조건에서 보호효과를 보이지 않았다. 허혈 후 20분간 산소와 포도당을 재공급한 경우 verapamil은 ATP 함량과 lactate 유리에 보호효과를 보였다. 한편 비타민 E는 20분 허혈 조건에서의 lactate 유리와 60분 허혈시의 MDA 유리 증가에 대해 감소효과를 보였다. 이상의 결과는 칼슘길항제와 비타민 E가 랫트 뇌절편에서의 허혈성 생화학적 손상을 방지함으로 나타난 결과로 해석되며, 칼슘갈항제의 효과가 비타민 E보다 우수함으로 미루어 칼슘길항제는 허혈성 뇌손상에 예방 및 보고효과를 보일 것으로 믿어졌다.

• Bulletin of the Korean Chemical Society
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• 제34권2호
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• pp.549-552
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• 2013

An efficient and alternative synthesis of enantiomerically pure (+)-(S)-4-(4-((4-chlorophenyl)(pyrid-2-yl)methoxy]piperidin-1-yl)butanoic acid, bepotastine (1) is described. The key resolution of (R/S)-bepotastine l-menthyl ester (3) is achived via diastereomeric salt crystallization using N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA) as the resolving agent to provide (S)-bepotastine l-menthyl ester (S)-3. Hydrolysis of (S)-bepotastine l-menthyl ester (S)-3 afforded the desired bepotastine (1) with good yields and enantiopurity (> 99%). Finally, bepotastine besilate (4) and bepotastine calcium (5) are achived by salt formation of bepotastine (1) with benzene sulfonic acid and calcium salt respectively. The reaction conditions were optimized to make suitable for commercial scale production.

• Archives of Pharmacal Research
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• 제14권3호
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• pp.242-248
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• 1991

Antihypertensive effect of YH 334 was examined in various experimental hypertension rat models and the systemic and regional hymohynamic profiles of the compound were investigated in conscious spontaneously hypertensive rats (SHR). The antiypertensive potensive potency of YH 334 is found to be more than 10 times stronger than that of nitrendipine in the all hypertensive models. The effective doses to lower the initial blood pressure by 20% $(ED_{20})$ of YH334 were 1.4 mg/kg in normotensive rats (NR), 0.7 mglkg in SHR. 0.1 mg/kg in DOCA salt hypertensive rats (DHR) and 0.4 mg/kg in renal hypertensive rats (RHR), and the $ED_{20}$ values of nitrendipine were 15.8 mg/kg in NR, 7.1 mg/kg in SHR, 1.7 mg/kg in DHR and 4.8 mg/kg in RHR. The primary hemodynamic effect hemodynamic profile is similar to that of nitrendipine. Both compounds seem to produce potent antihypertensive effects by lowering peripheral resistance in the skeletal muscles. In the organ bath study using isolated rabbit aorta, YH 334 was found to be a potent voltage dependent calcium channel blocker without significant inhibitory effect on the receptor operated calcium channels like the most of other dihydropyridine type calcium antagonists. Furthermore, YH334 showed acute diuretic and natriuretic effects in conscious SHR, which may render the unnecessary restriction of sodium in the diet of those patients on long term hypertension therapy. This effect would provide an additional benefit to its potent antihypertensive activity.

• Journal of Yeungnam Medical Science
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• 제9권2호
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• pp.359-381
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• 1992

Benzodiazepine계 약물들은 진정 최면제의 대표적인 약물로서, 중추신경계에서의 그 작용은 gamma amino butyric acid(GABA) 수용체와 짝지워져 있는 benzodiazepine 수용체를 통해서 나타나며 또한 뇌에 있는 synaptosome에서 전위 의존성 calcium channel을 통한 calcium의 섭취를 억제함으로써 진정작용 및 최면 작용이 나타난다. 이와 아울러 말초 장기에서도 benzodiazepine 수용체와 GABA 수용체가 발견 되었는데 이들의 기능과 상호관계는 잘 알려져 있지 않다. 이에 본 실험에서는 benzodiazepine계통의 대표적인 약물이며 중추신경과 말초 장기에 동시에 작용하는 diazepam이 흰쥐 적출자궁의 자발 수축 및 oxytocin 유발 수축에 미치는 영향을 검색하고, 이러한 diazepam의 효과와 GABA 수용체 및 calcium과의 상호관계를 검색함으로써 그 작용기전을 추구해 보기 위하여 다음과 같은 실험을 하였다. 난소를 제거한 후 estrogen(17 beta-estradiol : $500{\mu}g/kg/day$)을 4일 동안 전 처치한 흰쥐의 자궁을 적출하여 등척성 장력을 측정함으로써 그 수축력의 변화를 관찰하였다. Diazepam과 GABA 수용체 효현제 및 그 봉쇄제들이 자궁절편의 자발 수축과 oxytocin 유발 수축에 미치는 영향을 검색하였고, 또 이들 약물의 작용에 관련된 calcium 동원기전에 대하여 관찰하여 다음과 같은 결과를 얻었다. Diazepam은 흰쥐 적출자궁의 자발수축 및 oxytocin 유발수축을 농도 의존적으로 억제하였다. GABA, GABA A 수용체 효현제인 muscimol, GAGA A 수용체의 상경적 봉쇄제인 bicuculline, GABA A 수용체의 비상경적 봉쇄제인 picrotoxin, GABA B 수용체 효현제인 boclofen, 그리고 GABA B 수용체 봉쇄제인 delta-aminovaleric acid는 흰쥐 적출 자궁의 자발 수축 및 oxytocin 유발수축에 아무런 영향을 미치지 않았다. 자발 수축 및 oxytocin 유발수축에 대한 diazepam의 억제 작용은 GABA 수용체 효현제 및 봉쇄제의 영향을 받지 않았다. 그러나 bicuculline은 diazepam의 억제 작용에 상가적으로 작용하였는데, bicuculline의 이러한 작용은 muscimol에 의해서 길항되지 않았다. 정상 PSS 내에서 diazepam에 의해 억제되었던 자발수욱 및 oxytocin유발수촉은 calcium의 첨가 및 calcium inophore인 A23187의 첨가로 일부 회복되었다. Calcium 배제 용액내에서는 diazepam이 calcium 첨가로 인한 수축력 회복을 방해하였으며 calcium inophore인 A23187에 의한 수축력 증가는 막지 못하였다. 또 세포외액에 calcium이 결핍된 상태에서는 oxytocin 자체에 의한 수축을 방해하지 못하였으나 이어 첨가된 calcium에 의한 oxytocin 유발 수축의 증가는 일부 억제하였다. 이상의 실험결과로 미루어 볼 때 diazepam은 자궁의 자발수측 및 oxytocin 유발 수축을 억제할 수 있으며, 이러한 작용은 GABA 수용체 의존성이 아닌 세포외액의 calcium의 유입을 억제함으로써 나타나는 것으로 사료된다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.252-252
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• 1996

We Investigated the peripheral excitatory effect of capsaicin and KR-25018, a newly synthesized capsaicin derivative which was demonstrated to have a potent analgesic activity. KR-25018 and capsaicin were found to be both potent efficacious contractors of isolated guinea pig bronchial smooth muscle. KR-25018 was equipotent with capsaicin and [Sar$\^$9/,Met(O$_2$)$\^$11/]-substance P, 10-fold more potent than histamine and 10-fold less potent than (${\beta}$ -Ala$\^$8/)-neurokinin A(4-10), and their -log(M)EC$\_$50/ values were 6.94${\pm}$0.08, 6.86${\pm}$0.05, 6.96${\pm}$0.07, 5.64${\pm}$0.04, 7.96${\pm}$0.02, respectively. Contractile responses to KR-25018 and capsaicin were potentiated by phosphoramidon (1 ${\mu}$M), an inhibitor of neuropeptide-inactivating endopeptidase, but completely abolished in a calcium-free medium. These responses to KR-25018 and capsaicin were unaffected by the NK-1 antagonist CP96345 (1${\mu}$M), partially inhibited by the NK-2 antagonist SR48968 (1 ${\mu}$M) but almost completely abolished by a combination of the antagonists. A vanilloid receptor antagonist capsazepine competitively antagonized the responses to both KR-25018 and capsaicin (pA$_2$: aganst KR-25018, 5.98${\pm}$0.47; against capsaicin, 5.80${\pm}$0.31), and a capsaicin-sensitive cation channel antagonist ruthenium red caused significant reduction in the maximum responses to KR-25018 and capsaicin (pD'$_2$: against KR-25018, 4.61${\pm}$0.33; against capsaicin 4.96${\pm}$0.21). In conclusion, the present results suggest that KR-25018 and cpasaicin act on the same vanilloid receptor inducing the influx of calcium through ruthenium red-sensitive cation channel and produce contractile responses via the release of tachykinins that act on both NK-1 and NK-2 receptor subtypes.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.625-637
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• 1997

Calcium ions are implicated in a variety of physiological functions, including enzyme activity, membrane excitability, neurotransmitter release, and synaptic transmission, etc. Calcium antagonists have been known to be effective for the treatment of exertional angina and essential hypertension. Selective and nonselective voltage-dependent calcium channel blockers also have inhibitory action on the acute and tonic pain behaviors resulting from thermal stimulation, subcutaneous formalin injection and nerve injury. This study was undertaken to investigate the effects of iontophoretically applied $Ca^{++}$ and its antagonists on the responses of WDR (wide dynamic range) cells to sensory inputs. The responses of WDR cells to graded electrical stimulation of the afferent nerve and also to thermal stimulation of the receptive field were recorded before and after iontophoretical application of $Ca^{++}$, EGTA, $Mn^{++}$, verapamil, ${\omega}-conotoxin$ GVIA, ${\omega}-conotoxin$ MVIIC and ${\omega}-agatoxin$ IVA. Also studied were the effects of a few calcium antagonists on the C-fiber responses of WDR cells sensitized by subcutaneous injection of mustard oil (10%). Calcium ions and calcium channel antagonists ($Mn^{++}$, verapamil, ${\omega}-conotoxin$ GVIA & ${\omega}-agatoxin$ IVA) current-dependently suppressed the C-fiber responses of WDR cells without any significant effects on the A-fiber responses. But ${\omega}-conotoxin$ MVIIC did not have any inhibitory actions on the responses of WDR cell to A-fiber, C-fiber and thermal stimulation. Iontophoretically applied EGTA augmented the WDR cell responses to C-fiber and thermal stimulations while spinal application of EGTA for about $20{\sim}30\;min$ strongly inhibited the C-fiber responses. The augmenting and the inhibitory actions of EGTA were blocked by calcium ions. The WDR cell responses to thermal stimulation of the receptive field were reduced by iontophoretical application of $Ca^{++}$, verapamil, ${\omega}-agatoxin$ IVA, and ${\omega}-conotoxin$ GVIA but not by ${\omega}-conotoxin$ MVIIC. The responses of WDR cells to C-fiber stimulation were augmented after subcutaneous injection of mustard oil (10%, 0.15 ml) into the receptive field and these sensitized C-fiber responses were strongly suppressed by iontophoretically applied $Ca^{++}$, verapamil, ${\omega}-conotoxin$ GVIA and ${\omega}-agatoxin$ IVA. These experimental findings suggest that in the rat spinal cord, L-, N-, and P-type, but not Q-type, voltage-sensitive calcium channels are implicated in the calcium antagonist-induced inhibition of the normal and the sensitized responses of WDR cells to C-fiber and thermal stimulation, and that the suppressive effect of calcium and augmenting action of EGTA on WDR cell responses are due to changes in excitability of the cell.

• Bulletin of the Korean Chemical Society
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• 제23권1호
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• pp.143-144
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• 2002

• 약학회지
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• 제32권6호
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• pp.402-414
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• 1988

In order to clarify the receptor types and mechanisms underlying the positive inotropic effect of dopamine on the mammalian ventricular myocardium, the action potential, its first derivatives and isometric contraction of the rabbit papillary muscle were recorded using a force transducer and glass capillary microelectrodes filled with 3M KCl. The results were as follows; (1) In normal Tyrode solution, the contractile force was increased and duration of action potential was shortened with increments of dopamine concentration ($10^{-6}-10^{-4}M$). (2) The dose-response curve was markedly shifted to the right by pretreatment with reserpine (5mg/kg i.p., 24hrs prior to the experiment). (3) In 19mM $K^+-Tyrode$ solution, the duration of action potential, maximum rate of rise (V_{max}) of action potential and overshoot were significantly increased with increments of dopamine concentration ($10^{-6}-10^{-4}M$). (4) The inotropic effect of dopamine on the rabbit papillary muscle pretreated with reserpine was antagonized by atenolol ($10^{-6}M$), but not by phentolamine ($3{\times}10^{-6}M$). (5) In rabbit papillary muscle partially depolarized by 19mM $K^+-Tyrode$ solution, slow electrical response (calcium mediated action potential) as well as contraction were restored by dopamine ($10^{-4}M$); this restoration was blocked by calcium antagonists ($3{\times}10^{-5}M$ $LaCl_3{\cdot}6H_2O$, $3{\times}10^{-6}M$ diltiazem) or ${\beta}-adrenoceptor$ antagonist ($3{\times}10^{-6}M$ atenolol), but not affected by ${\alpha}-adrenoceptor$ antagonist ($10^{-5}M$ phentolamine, $3{\times}10^{-6}M$ yohimbine) or vascular dopaminergic receptor antagonist ($10^{-5}M$ haloperidol). The above results may be interpreted as that the positive inotropic effect of dopamine through both direct and indirect action are caused by increase in slow inward current ($Ca^{2+}$ influx into themyocardial cell), and the direct action is mainly due to the stimulation of ${\beta}-adrenoceptors$ in the rabbit papillary muscle.

• Journal of Trauma and Injury
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• 제19권2호
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• pp.173-177
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• 2006

Hydrofluoric acid is a colorless gas or fuming liquid with a strong, irritating odor. Hydrofluoric acid burns are uncommon; however, if severe burn occur, they caused death from systemic effects, such as fatal cardiac arrthmia. We experienced two cases of hydrofluoric acid chemical burns on digits. These patients had typical clinical features of hydrofluoric acid chemical burns, such as pulsating pain at the burn site, as well as ischemic and necrotic skin changes. The hydrofluoric acid chemical burn was confirmed by a history of exposure. Subsequently, we made a calcium gluconate gel by mixing 20% calcium gluconate, an antagonist against hydrofluoric acid, with lubricant, and we injected 10% calcium gluconate subcutaneously when they complained of pain rated at higher than 5 on the pain scale. Simultaneously, we monitored the patients' electrocardiographs and checked their serum total calcium, ionized calcium, and magnesium levels serially. Clinical presentations and the emergency management of hydrofluoric acid chemical burns were reviewed along with the current literature. These patients were discharged without any significant complications.