• The Korean Journal of Physiology and Pharmacology
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• 제2권4호
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• pp.461-469
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• 1998

Tetrahydroisoquinoline (THI) alkaloids can be considered as cyclized derivatives of simple phenylethy-lamines, and many of them, especially with 6,7-disubstitution, demonstrate relatively high affinity for catecholamines. Two -OH groups at 6 and 7 positions are supposed to be essential to exert ?${\beta}-receptor$ activities. However, it is not clear whether -OH at 6,7 substitution of THIs also shows ?${\alpha}-adrenoceptor$ activities. In the present study, we investigated whether -OH or $-OCH_3$ substitutions of 6,7 position of THIs differently affect the ?1-adrenoceptor affinity. We synthesized two 1-naphthylmethyl THI alkaloids, $1-{\beta}-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline$ HBr (YS 51) and $1-{\beta}-naphthylmethyl-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline$ HCl (YS 55), and their pharmacological actions on ?${\alpha}_1-adrenoceptor$ were compared. YS 51 and YS 55, concentration-dependently relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 ${\mu}M$) in which $pEC_{50}$ were $5.89{\pm}0.21$ and $5.93{\pm}0.19$, respectively. Propranolol (30 nM) did not affect the relaxation-response curves to YS 51 and YS 55. Concentration-response curves to PE were shifted to right by the pretreatment with YS 51 or YS 55. The $pA_2$ values of YS 51 and YS 55 showed $6.05{\pm}0.24$ and $5.88{\pm}0.16$, respectively. Both probes relaxed KCl (65.4 mM)-contracted aorta and inhibited $CaCl_2-induced$ contraction of PE-stimulated endothelium- denuded rat thoracic aorta in $Ca^{2+}-free$ solutions. In isolated guinea pig papillary muscle, 1 and 10 ${\mu}M$ YS 51 increased contractile force about 4- and 8- fold over the control, respectively, along with the concentration-dependent increment of cytosolic $Ca^{2+}$ ions. While, 10 ${\mu}M$ YS 55 reduced the contractile force about 50 % over the control and lowered the cytosolic $Ca^{2+}$ level, in rat brain homogenates, YS 51 and YS 55 displaced $[^3H]prazosin$ binding competitively with Ki 0.15 and 0.12 ${\mu}M$, respectively. However, both probes were ineffective on $[^3H]nitrendipine$ binding. Therefore, it is concluded that two synthetic naphthylmethyl-THI alkaloids have considerable affinity to ?1-adrenenoceptors in rat aorta and brain.

• 약학회지
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• 제34권3호
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• pp.180-191
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• 1990

A comparison was made of the effects of selective ${\alpha_1}-adrenoceptor$ agonist phenylephrine and selective ${\alpha_2}-adrenoceptor$ agonist clonidine on endothelium-containing and endothelium-denuded rings of the rat aorta. In the case of phenylephrine, removal of endothelium increased sensitivity 2.5 fold at $EC_{50}$ level and maximum contractive response 1.4 fold. In the case of clonidine, which gave only 15% of maximum contractive response given to phenylephrine on endothelium-containing rings, removal of the endothelium increased sensitivity 5.6 fold at $EC_{50}$ level and maximum contractive response 5 fold, which was about 55% of that given by phenylephrine. In endothelium-denuded ring, phenylephrine-induced contraction tended to be more increased in tonic contraction than in phasic contraction as compared to that in endothelium-containing ring, while clonidine-induced contraction was monophasic and was increased only in tonic contraction. In the calcium-free solution or in the presence, of verapamil, contraction stimulated by clonidine was almost abolished while that stimulated by phenylephrine produced only phasic contraction. The depression of sensitivity to these agonists in rings with endothelium appeared to be due to the vasodepressor action of endothelium derived relaxing factor (EDRF), because hemoglobin, a specific blocking agent of EDRF, abolished this depression. It is unlikely that the endothelium-dependent relaxation was due to stimulation of release of EDRF, because clonidine did not produce endothelium-dependent relaxation in 5-hydroxytryptamine-precontracted ring even when its contractile action was blocked by the ${\alpha_1}-adrenoceptor$ antagonist, prazosin. When the efficacy of phenylephrine was reduced to about the initial efficacy of clonidine by pretreatment with dibenamine, the contraction-response curves for phenylephrine became very similar to the corresponding curves obtained for clonidine before receptor inactivation. In the dibenamine-treated rings, contraction of phenylephrine was abolished in calcium-free solution or in the presence of verapamil like that obtained for clonidine before receptor inactivation. These results suggest that EDRF spontaneously released from endothelium depress contraction more profoundly in a case of an agonist with low efficacy and the phenylephrine-induced contraction was totally dependent on extracellular calcium as was that obtained for clonidine when the efficacy of phenylephrine was reduced to that of clonidine by irreversible inactivation of ${\alpha_1}-adrenoceptor$ with dibenamine.

• The Korean Journal of Physiology and Pharmacology
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• 제2권3호
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• pp.323-330
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• 1998

Tetrahydroisoquinoline (THI) alkaloids can be considered as cyclized derivatives of simple phenylethylamines. Many of them, especially with 6,7-disubstitution, demonstrate a relatively high affinity for catecholamines. Present study examines the pharmacological action of limited series of THI, using rats' isolated atria and aorta. In addition, a $[^3H]$ prazosin displacement binding study with THI compounds was performed, using rat brain homogenates to investigate whether these probes have ?${\alpha}$-adrenoceptor affinity. We also compared the vascular relaxation potency of these probes with dobutamine. YS 49, YS 51, higenamine and dobutamine, concentration-dependently, relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 ${\mu}M$) in which $pEC_{50}$ were $5.56{\pm}0.32$ and $5.55{\pm}0.21$, $5.99{\pm}1.16$ and $5.57{\pm}0.34$, respectively. These probes except higenamine also relaxed KCl (65.4 mM)-contracted aorta. In isolated rat atria, all THIs and dobutamine increased heart rate and contractile force. In the presence of propranolol, the concentration response curves of YS 49 and YS 51 shifted to the right and resulted in $pA_2$ values of $8.07{\pm}0.84$ and $7.93{\pm}0.11$, respectively. The slope of each compound was not deviated from unity, indicating that these chemicals are highly competitive at the cardiac ?${\beta}-adrenoceptors$. YS 49, YS 51, and higenamine showed ?${\alpha)-adrenoceptor$ affinity in rat brain, in which the dissociation constant $(K_i)$ was 2.75, 2.81, and 1.02 ${\mu}M$, respectively. It is concluded, therefore, that THI alkaloids have weak affinity to ${\alpha)_1-adrenoceptor$ in rat aorta and brain, respectively, while these probes show relatively high affinity for cardiac ${\beta}-adrenoceptors$. Thus, these chemicals may be useful in the treatment of congestive heart failure.

• Journal of Chest Surgery
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• 제34권6호
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• pp.485-489
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• 2001

배경: 수술 후 흉골 합병증을 유발하는 원인 인자들 중 흉골 봉합선의 견고성이 차지하는 비중은 매우 크다. 본 저자들은 흉골 봉합 방법에 따른 흉골 열개 및 감염의 발생빈도를 조사하여 합병증이 적은 가장 효과적인 흉골 봉합 방법을 찾고자 하였다. 대상 및 방법: 1995년 1월부터 1999년 7월까지 개심술을 받았던 환자들중 45세 이상의 환자 489예를 대상으로 하였다. 봉합 철사 6개로 단순 봉합을 한 159예, 흉골병에 2개의 단순 봉합 후 3개의 8자형 봉합을 한 119예, 각 늑간에 2개씩 10개의 단순 봉합한 150예, 단순 봉합과 8자형 봉합을 혼합하여 사용한 61예를 대상으로 하였다. 234예에서 판막수술을, 213예에서 관상동맥 우회술을 시행하였으며, 42예에서 그 외의 수술을 하였다. 결과: 총 12예(2.5%)에서 흉골 열개 및 감염의 합병증이 발생하였다. 수술 후 흉골 절개부의 합병증은 철사 6개를 이용한 단순 봉합 환자군의 3.1%(5/159)에서, 8자형 봉합 환자군의 3.4%(4/119)에서, 철사 10개를 이용한 겹치기 단순 봉합 환자군의 2.0%(3/150)에서 발생하였으며, 단순 봉합과 8자형 봉합을 혼합하여 사용한 환자 군에서는 합병증이 없었다(교차비에서 유의성은 없으나 다른 세 봉합방법에 대한 상대위험도에서는 유의성을 보임). 판막수술을 받은 환자군의 7예(3.0%), 관상동맥 우회술을 받은 환자군의 5예(2.3%)에서 흉골 합병증이 발생하여 수술 종류에 따른 흉골 감염의 차이는 없었으며, 당뇨병은 흉골 합병증의 독립적인 위험인자가 될 수 있었다(교차비 및 다량분석에서 p = 0.00). 결론: 흉골 봉합 때 단순 봉합과 8자 봉합의 혼합방법을 사용함으로써 흉골봉합이 용이하고 수술 후 흉골의 열개나 감염의 합병증을 줄일 수 있다고 생각된다. 비해 64.5 $\pm$ 4.6%, 63.8 : 4.4%로 유의하게 개선된 소견을 보였으나(P<0.05), ll, III군에서 reserpine 및 prazosin으로 전처치 조건을 차단한 V, Vl군은 동일한 재관류 시간이 경과한 후 developed pressure는 52.2 $\pm$ 5.2%, 49.8 $\pm$ 5.7%로 단위시간당 수축기 좌심실압의 회복율은 54.8 $\pm$ 5.1%, 53.3 $\pm$ 3.6%로 II, III군에 비해 유의한 회복율의 감소를 보였고 이러한 회복율은 I군에 비해 유의한 차가 없었다. 결론: 교감신경 $\alpha$-수용체 작용약물에 의한 약물학적 전처치는 재관류 후 심근기능 회복에 유익한 효과를 나타냈으며, 이러한 전처치 효과는 교감신경계 신경전달물질의 고갈이나 $\alpha$1-수용체 차단제에 의해 소멸되는 것으로 보아 전처치에 의한 심근보호효과는 교감신경계 전달물질 및 $\alpha$1-수용체를 통해 유도됨을 알 수 있다.380$\pm$71 mL, p=0.05).방 및 치료에 도움이 될 수 있는 물질을 개발할 가치가 있다고 사료된다을 공급한 대조구에 비해 높았다. 어미의 성 성숙 및 산란은 두 번의 실험에서 대조구보다 저염분구에서 원만히 이루어졌다. 암컷 성숙 개체의 경우 1차 실험은 대조구 6마리, 저염분구 12마리였으며, 2차 실험은 대조구 5마리, 저염분구 12마리였으며, 2차 실험은 대조구 5마리, 저염분구 14마리로서 성숙유도에 있어 염분의 조절에 의한 성숙이 이루어진 것을 알 수 있다. 산란 시기는 1차 실험에서 대조구나 저염분구의 산란 개시 시점이 거의