• Biomolecules & Therapeutics
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• 제4권4호
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• pp.373-377
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• 1996

The effect of potassium channel openers, KR-30450, KR-30818 and lemakalim have been compared against several spasmogens in guinea pig bronchi. In guinea pig bronchi, KR-30450 had a greater relaxant effect than lemakalim and KR-30818 against tone induced by histamine $10^{-5}M$ ($EC_{50}$ $\mu$M: KR-30450, 0.108$\pm$0.077; KR-30818, 0.403$\pm$0.023; lemakalim, 0.968$\pm$0.036) and prostaglandin $F_{2\alpha} 3\times10^{-6} M$ ($EC_{50}$ $\mu$M: KR-30450, 0.018$\pm$0.001; KR-30818, 0.028$\pm$0.003; lemakalim, 0.138$\pm$0.019). Relaxant effect of KR-30450 and KR-30818 were significantly reduced by 20 min pretreatment of tissues with $10^[-6}$ M glibenclamide, a selective blocker of ATP-sensitive potassium channel. Against acetylcholine-induced tone in guinea pig bronchi, however, these compounds had little effect. In summary, KR-30450 and KR-30818 showed greater relaxant effect than lemakalim in guinea pig bronchi (KR-30450>KR-30818>lemakalim). These relaxant actions are suggested to be mediated at least in part by a mechanism which involves the opening of ATP-sensitive potassium channel.

• 약학회지
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• 제41권1호
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• pp.139-146
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• 1997

In the present study, capsaicin-induced desensitization of peripheral sensory nerves were investigated by using guinea pig bronchi, in which these nerves are stimulated with cap saicin to produce a contractile response via the release of sensory neuropeptides such as substance P and neurokinin A. The contractile response to capsaicin was inhibited by the combination of CP96345 and SR 48968 suggesting that the excitatory effect of capsaicin is mediated via both the tachykinin NK-1 and NK-2 receptor. Capsaicin produced in vitro-desensitization in dose-dependent manner, but after this in vitro-desensitization the response to NK-1 and NK-2 receptor agonist did not change. Systemic administration (s.c.) of capsaicin also desensitized significantly bronchial tissues but could not produce any change in the contractile response to the selective agonists of NK-1 and NK-2 receptor. Therefore, the present results suggest that functional desensitization to capsaicin-induced contractile response in guinea pig bronchi does not involve NK-1 and NK-2 receptor, while excitatory effect of capsaicin is mediated via both NK-1 and NK-2 receptor. In conclusion, it is suggested that capsaicin- induced excitation and desensitization involves somewhat different pathways.

• Biomolecules & Therapeutics
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• 제3권4호
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• pp.256-259
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• 1995

Antinociceptive and desensitizing effects of systemically administered capsaicinoids (capsaicin and KR25018) were investigated in guinea pig. Nociceptive sensitivity to chemical stimulus was examined to test sensory function, and the content of substance P-like immunorractivity (SP-LI) in bronchi was determined as a peripheral marker of capsaicin-sensitive primary afferent neurons. Guinea pigs were pretreated s.c. with several doses of capsaicin (1,2.5,5, 10 mg/kg) or KR25018 (1, 2.5, 5, 10 mg/kg) one week prior to the experiments. Frequency of eye wiping was significantly decreased by capsaicin and KR25018 in a pretreatment dosedependent manner. In capsaicin- or KR25018-pretreated guinea pigs, there was a significant loss of SP-LI in bronchial tissue extracts. In summary, a newly synthesized capsaicin analogue H725018 exhibited antinociceptive effect against chemical stimulus in guinea pig, with comparable potency to capsaicin. This desensitizing activity of capsaicin or KR25018 might be related to the loss of SP-LI in peripheral afferent nerves.

• 한국식품위생안전성학회지
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• 제9권3호
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• pp.163-168
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• 1994

In the present study we investigated the peripheral function of capsaicin and KR-25018, a newly synthesized capsaicin derivative, which was demonstrated to have a potent analgesic activity through different mechanism from morphine and nonsteroidal antiinflammatory drugs. Capsaicin (10-8~10-5 M) and KR-25018 (10-8~10-5 M) produced concentration-dependent contractions of the isolated guinea pig bronchi. There were no significant differences in the maximum response and the EC50 values (EC50: 0.137$\pm$0.025 $\mu$M and 0.097$\pm$0.031 $\mu$M for capsaicin and KR-25018, respectively, P>0.05). Phosphoramidon (10 $\mu$M) and indomethacin (10 $\mu$M) had no significant effect on contractile response to the submaximal concentration range of capsaicin and KR-25018 (3$\times$10-9~3$\times$10-7 M). The response to KR-25018, like that to capsaicin, was significantly inhibited by ruthenium red with reduction in the maximum response, which is indicative of non-competitive antagonism. A further common feature of the responses to capsaicin and KR-25018 in the guinea pig bronchi was their sensitivity to capsazepine. Capsazepine caused a rightward parallel shift in concentration-response curves obtained by capsaicin and KR-25018. the pA2 values of capsazepine were 5.90 and 5.99 against capsaicin and KR-25018 response, respectively. In conclusion, KR-25018 and capsaicin exert their contractile effects in the isolated guinea pig bronchial muscle by common mechanisms, probably via the activation of a specific receptor.

• Advances in Traditional Medicine
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• 제8권3호
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• pp.286-294
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• 2008

We have studied the possible mechanism of anti-asthmatic action of ethanolic extracts of dried seeds of Lepidium sativum (EXLS, 400 mg/kg) using various experimental models. EXLS produced an increase in the Pre-Convulsion Dyspnoea time induced by histamine and acetylcholine aerosol, a significant reduction in the elevated leucocyte counts in the Broncho-Alveolar Lavage fluid of sensitized guinea-pigs and reduction in the paw edema volume as compared to the control rats. Treatment with EXLS also produced decrease in the elevated histamine release from the sensitized guinea-pig lungs. The anti-asthmatic anti-inflammatory responses of EXLS was supported by improvement in microscopic changes like infiltration of inflammatory cells, submucosal edema, epithelial desquamation and reduced lumen size of the bronchi. The $pD_2$ values of histamine in tracheal chain and taenia-coli were significantly greater and that in lung strip was lower in the sensitized animals as compared to control. Treatment of sensitized guinea pigs with EXLS significantly decreased $pD_2$ values of histamine in all three preparations. Our data suggest the prevention of hyper-responsiveness in bronchial smooth muscles and inhibition of the immediate hypersensitive reaction, histamine release in the lungs and the infiltration of various inflammatory cells as the possible mechanisms of anti-asthmatic activity of EXLS.

• 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.

• Tuberculosis and Respiratory Diseases
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• 제45권4호
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• pp.697-704
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• 1998

연구배경: 천식은 기관지에 호산구의 침착을 동반한 염증을 특징으로 한다. 말초 혈액에 존재하던 호산구가 천식 반응시 기관지 조직 내로 침착되는 과정에는 여러 종류의 호산구 화학 주성인자들이 관여한다. Chemokines은 염증 부위에 백혈구를 동원시키는 중요한 화학 주성 물질 중의 하나이다. 호산구 화학 주성에 관여하는 chemokines으로는 RANTES, MCP-3 등이 있지만 호산구뿐 아니라 다른 종류의 세포에도 작용한다. 최근에 호산구에만 특이적으로 작용하여 조직에 호산구의 침착을 유도하는 새로운 chemokine인 eotaxin이 cloning되었으며 호산구가 혈중에 증가되거나 조직에 침착하는 여러 알러지 질환의 중요한 매개불질로 연구되고 있다. 최근 연구에 의하면 사람에서의 eotaxin은 호산구의 강력한 화학 주성 물질로 조직내의 호산구 침착의 주요 원인이며 천식에서 중요한 매개물질일 것으로 추측된다. 따라서 본 연구에서는 천식 환자의 기관지 조직에서 eotaxin mRNA의 발현을 조사하고 기관지 조직 내 호산구의 침착과의 관계를 조사하였다. 연구방법: 최근 수개월간 특별한 치료없이 폐기능의 저하와 천식 증상을 갖고 있었던 천식 환자 4예(A 군), 흡입용 혹은 경구용 스테로이드 사용을 유지하면서 정상 범위의 폐기능을 유지하고 증상이 없었던 천식 환자 3예(B 군), 정상 대조군 2예(C 군), 최근 3개월 이상 어떤 천식 치료제를 사용하지 않고도 정상 범위의 폐기능을 유지하고 증상이 없었던 천식 환자 2예(D군), 천식의 악화로 입원하여 기관지 확장제와 경구용 혹은 정맥용 스테로이드를 10일 이내 사용하여 증상은 호전되었으나 폐기능의 저하를 보였던 2예(E 군)를 대상으로 하였다. 모든 대상 환자는 기관지 내시경을 이용하여 기관지 조직 검사를 시행했다. 조직에서 분리된 RNA로 부터 semi-quantitative RT-PCR를 시행하였다. 양성 대조군인 GAPDH mRNA에 대한 eotaxin mRNA의 비(ratio)를 densitometer를 이용하여 정량화하여 eotaxin mRNA의 발현을 간접적으로 측정하였다. Eotaxin mRNA의 발현과 기관지 조직내의 호산구 침착 정도의 상호 관계를 관찰하였다. 결 과: Eotaxin mRNA의 발현은 최근 수개월간 특별한 치료 없이 폐기능의 저하와 천식 증상을 갖고 있었던 현증 천식 환자 4예(A 군), 최근 수개월간 천식 치료를 받지 않았지만 천식 증상이 없었던 2예 중 1예(D군), 천식이 악화되어 경구 혹은 정맥 스테로이드를 10일간 사용하였던 2예(E 군)에서 나타났다. Densitometer로 eotaxin mRNA의 발현을 측정한 결과 A군은 4예 모두에서 높았으며 D, E 군은 상대적으로 낮았다. Submucosa 내의 호산구 침착과 eotaxin mRNA의 발현은 상관 관계가 있었다 결 론: 천식환자 기도에서 eotaxin의 발현은 증가되며 호산구의 기도내 침착을 유도하는 화학 주성 물질로 생각된다. 따라서 기도내 eotaxin mRNA의 발현은 천식의 발병의 중요한 요인으로 사료된다.