• 약학회지
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• 제32권2호
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• pp.129-136
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• 1988

Effects of the selective alpha-adrenoceptor agonists, clonidine, oxymetazoline and phenylephrine, on heart rate and contractile force were investigated in the isolated frog atria and it was attempted to examine the influence of adrenoceptor antagonist upon those. Clonidine produced dose-dependent negative chronotropic and positive inotropic effects. The negative chronotropic effect was significantly attenuated in the presence of prazosin and yohimbine but not propranolol. The positive inotropic effect was significantly attenuated by prazosin, yohimbine and propranolol. Oxymetazoline produced dose-dependent negative chronotropic and inotropic effects. The negative chronotropic effect was significantly attenuated in the presence of prazosin, which was partially augmented by yohimbine but was not affected by propranolol. The negative inotropic effect was not affected by propranolol but it was partially augmented by yohimbine and was partially attenuated by prazosin. Phenylephrine produced dose-dependent positive chronotropic and inotropic effects. The positive chronotropic and inotropic effect were significantly attenuated in the presence of propranolol but were not affected by prazosin and yohimbine. These results suggest that the negative chronotropic effect by clonidine and oxymetazoline is mediated by alpha-adrenoceptors, the positive chronotropic and inotropic effects by phenylephrine are mediated by beta-adrenoceptors, and alpha-adrenoceptors mediated the inhibitory chronotropic responses exists in the isolated frog atria.

• The Korean Journal of Physiology
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• 제21권2호
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• pp.179-189
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• 1987

Since it has been known that ryanodine has a potent negative inotropic effect on the cardiac muscle contractility (Jenden and Fairhurst, 1968), ryanodine has been a subject of intensive research (Frank and Sleator, 1975; Jones et al, 1978; Sutko et al, 1985). However, the underlying mechanism for the ryanodine dependent negative inotropic effect is still uncertain. In this study, the effects of ryanodine on the generation and relaxation of contracture due to Na-withdrawal and on the force-frequency relationship of heart muscles isolated from rats and guinea pigs were measured in an effort to understand the underlying mechanism of the ryanodine-induced negative inotropy. Results are summerized as follows: 1 ) Ryanodine significantly reduced the contractility of heart muscles produced at low frequency of stimulation, but showed a little effect on the contractility at high frequency stimulation. 2) Ryanodine, at the concentrations ranging from $10^{-6}\;M$ to $10^{-8}\;M$, had no significant effect on the Na-dependent relaxation of Na-withdrawl contracture. 3) Ryandoine significantly reduced the amplitude of the Na-withdrawl contracture, and this inhibitory effect was reinforced by procaine, antiagonized by caffeine and high potassium. From these results, it may be concluded that the negative inotropic effect of ryanodine is mainly due to an inhibition of calcium release from sarcoplasmic reticulum.

• The Korean Journal of Physiology
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• 제20권2호
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• pp.175-183
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• 1986

Since it was proposed that vanadate may be an ‘ideal endogenous regulator of the $Na^+,\;K^+-ATPase$ activity (Cantley et at, 1979), vanadate has been a subject of intensive research and a variety of its physiological effects have been described (Nechay, 1984). In isolated guinea pig heart muscle vanadate shows a positive inotropic effect on ventricular muscle, while it induces a negative inotropic effect on atrial muscle. But its underlying mechanism has not been elucidated so far. Therefore, in this study the flux rates of calcium ion into and from guinea pig heart muscle were measured to throw some light on the underlying mechanism, because those rates have been known to be closely related to the cardiac contractility and the results are summarized as follows: 1) Calcium efflux rates from the intracellular $Ca^{++}$ pool (compartment 4) of both guinea pig left atrium and right ventricle were significantly reduced by vanadate and their pool sizes were significantly increased by vanadate. 2) The magnitude of calcium influx into left atrium was reduced by vanadate, While the magnitude of calcium influx into right ventricle was not affected by vanadate. From these results, it may be concluded that the positive inotropic effect of vanadate on the ventricular muscle was due to a reduced efflux rate of calcium ion and its negative inotropic effect on atrial muscle was resulted from a reduced influx of calcium ion.

• The Korean Journal of Physiology
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• 제29권2호
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• pp.203-216
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• 1995

The effects of ${\alpha}_1-adrenergic$ receptor stimulation on membrane potential, intracellular $Na^+$ activity, and twitch force were investigated in ventricular muscles from guinea-pig hearts. Action potentials, intracellular $Na^+$ activity, and twitch force of ventricular papillary muscles were measured simultaneously under various experimental conditions. Stimulation of the ${\alpha}_1-adrenergic$ receptor by phenylephrine produced variable changes in action potential duration, a slight hyperpolarization of the diastolic membrane potential, a decrease in intracellular $Na^+$ activity, and a biphasic inotropic response in which a transient negative inotropic response was followed by a sustained positive inotropic response. These changes were blocked by prazosin, an antagonist of the ${\alpha}_1-adrenergic$ receptor, but not by atenolol, an antagonist of the ${\beta}-adrenergic$ receptor. This indicates that the changes in membrane potential, intracellular $Na^+$ activity, and twitch force are mediated by stimulation of the ${\alpha}_1-adrenergic$ receptor, but not by stimulation of ${\beta}-adrenergic$ receptor. The decrease in intracellular $Na^+$ activity was not observed in quiescent muscles, depending on the rate of the action pontentials in beating muscles. The intracellular $Na^+$ activity decrease was substantially inhibited by tetrodotoxin. However, the decrease in intracellular $Na^+$ activity was not affected by an inhibition of the $Na^+-K^+$ pump. Therefore, the decrease in intracellular $Na^+$ activity mediated by the ${\alpha}_1-adrenergic$ receptor appears to be due to a reduction of $Na^+$ influx during the action potential, perhaps through tetrodotoxin sensitive $Na^+$ channels. Our study also revealed that the decrease in intracellular $Na^+$ activity might be related to the transient negative inotropic response. The intracellular $Na^+$ activity decrease could lower intracellular $Ca^{2+}$ through the $Na^+-Ca^{2+}$ exchanger and thereby produce a decline in twitch force.

• 대한약리학회지
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• 제32권2호
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• pp.189-199
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• 1996

Myocardial ${\alpha}_1-adrenoceptors$ have been shown to mediate a biphaslc inotropic response that was characterized by a transient decline followed by a sustained increasing phase in guinea pig ventricular muscle. Recently one group reported that an ${\alpha}_1-adrenoceptors-induced$ intracellular $Na^+$ decrease is linked to fast $Na^+$ channel inhibition and another group reported that it is linked to $Na^+$-$K^+$ pump activation by ${\alpha}_{1b}-adrenoceptors$. But until now, its mechanism is not clear. Therefore, to see whether the $Na^+$channel or $Na^+-K^+$ pump is related to a decrease in intracellular $Na^+$ activity and/or the negative inotropic response, and which ${\alpha}_1-adrenoceptor$ subtype was involved in the decrease in intracellular $Na^+$activity by phenylephrine, we used conventional and sodium selective microelectrodes, and tension transducer to determine the effects of ${\alpha}_1-adrenergic$ stimulation on membrane potential, intracellular $Na^+$ activity, and twitch force in guinea pig ventricular muscles. $10^{-5}$ M Phenylephrine produced a slight hyperpolarization of the diastolic membrane potential, a decrease or increase in $a_N^i_a$, and a biphasic inotropic response. The negative inotropic response accompanied by a decrease in intracellular $Na^+$activity, whereas in muscles showing a remarkable positive inotropic response without initial negative inotropic effect was accompanied by an increase in intracellular $Na^+$ activity. The decrease in intracellular $Na^+$ activity was apparently inhibited by WB4101, an antagonist of the ${\alpha}_{1a}-adrenoceptors$. The decrease in intracellular $Na^+$ activity caused by phenylephrine was not abolished or reduced by a block of the fast $Na^+$ channels. $V_{max}$ also was not affected by phenylephrine. Phenylephrine produced an increase in intracellular $Na^+$ activity in the presence of a high concentration of extracellular $Ca^{2+}$ (in quiescent muscle) or phorbol dibutyrate, a protein kinase C activator(in beating muscle). These suggest that the ${\alpha}_{1a}-adrenoceptors-mediated$ decrease in intracellular $Na^+$ activity may be related to the protein kinase C.

• 약학회지
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• 제41권2호
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• pp.241-246
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• 1997

The effect of potassium channel openers, SKP-450, SKP-818 and lemakalim have been compared in rat heart and aorta. In rat isolated heart, SKP-450 had a greater negative inotrop ic effect than lemakalim and KR-30818 against left ventricular developed pressure (LVDP) and double product of heart rate and LVDP (DP). In addition, SKP-450 had a greater effect than lemakalim and KR-30818 in increasing coronary flow, indicating a more potent vasodilating effect in coronary artery. Negative inotropic effect and coronary vasodilating effect of SKP-450 and SEP-818 were significantly reduced by 10 min-perfusion with $10^{-6}M$ glyburide, a selective blocker of ATP-sensitive potassium channel. In rat aorta, SKP-30450 and SKP-30818 as well as lemakalim induced powerful concentration-dependent relaxations against norepinephrinc-induced tone ($EC_{50},\;{\mu}M$ : SKP-30450, $0.107{\pm}0.009$; SKP-30818, $0.476{\pm}0.022$ ; lemakalim, $0.565{\pm}0.039$ ). These relaxant effects were significantly reduced by pretreatment with glyburide. In sununary, SKP-30450 and SKP-30818 showed greater negative inotropic and vasorelaxant effect than lemakalim in rat aorta with order of potency of SKP-30450 > SKP-30818 > lemakalim. These actions are suggested to be mediated at least in part by a mechanism which involves the opening of ATP-sensitive potassium channel.

• 생약학회지
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• 제19권3호
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• pp.208-215
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• 1988

To investigate the experimental effects of Chunwangboshimdan which have been widely used for aterial or auricular flutter, neurosis, insomnia and disease caused by cardiac malfunction, we have done the effects on the central nervous and cardiovascular system. The result as follow; It inhibited the convulsion induced by caffeine, the writhing syndrome induced by acetic acid and the spontaneous movement. Furthermore it prolonged the sleeping time induced by thiopental-Na in mice. It also showed the negative inotropic action on the isolated heart of frog, the vasodilative action as to peripheral bloods of rabbit ear and the hypotensive action in the anesthetized rabbit.

• 생약학회지
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• 제18권4호
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• pp.241-248
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• 1987

Woohwangchungsim-Won has been widely used for the treatment of appoplexy, hypertension, arteriosclerosis, insomnia and cerebrovascular accident, etc in oriental hospital and pharmacy. In order to investigate the efficacy of Woohwangchungsim-Won, the water extract of it were bioassayed for isolated ileum, blood vessels, blood pressure, heart and diuresis. The results of this studies were as follows; Spontaneous motilities of isolated ileum of mice were strongly suppressed, and contraction of isolated ileum of mice and guinea-pigs induced by acetylcholine chloride, barium chloride and histamine were inhibited. Vaso-dilating action due to vascular smooth muscle relaxation in frogs and rabbits, and hypotensive action in anesthetized rabbits were noted. Negative inotropic action on the isolated frog heart and diuretic effect in rabbits were shown.

• 대한약리학회지
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• 제19권2호
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• pp.9-16
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• 1983

현재 사용되고 있는 강심제로는 디지탈리스 배당체가 유일한 약물이지란 그 안전역이 대단히 좁아서 보다 안전한 강심제의 개발이 요구되고 있다. 최근 강심작용이 현저할 뿐 아니라 안전역이 비교적 넓을 것으로 인정되는 higenamine이 개발되어 그 작용기전을 밝히려는 시도가 많이 있었다. 본 연구에서는 higenamine의 강심작용 기전을 규명하기 위한 연구의 일환으로 수축빈도-수축력 상관관계(interval-strength relationship)에 있어서 1) Rested-state수축력 2) Positive inotropic effect of activation(PIEA) 3) Negative inotropic effect of activation(NIEA)에 대한 higenamine의 영향을 $Ca^{++}$및 epinephrine과 비교 분석하였다. 실험결과 칼슘은 PIEA를 증가시키기 보다는 오히려 NIEA의 소멸을 촉진함으로써 강심작용을 나타내며 epinephrine 및 higenamine은 PIEA를 증가시키고 NIEA에는 거의 영향을 미치지 않았다.

• 생약학회지
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• 제17권4호
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• pp.272-279
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• 1986

This study was conducted about the effect of Shihogesikungang-tang on the central nervous system and cardiovascular system for the investigation of its clinical effect based on the Oriental medicinal references. The results of this study were summerized as follows; Analgesic activity as evaluated by the writhing syndrome in mice was significantly noted. A decrease effect of the spontaneous movement as estimated by wheel cage method, muscle relaxant effect as evaluated by the rotor rod method and the prolonged effect of sleeping time induced by thiopental-Na were significantly shown in mice. A antipyretic activity in febrile rats induced by the endotoxin was recognized. Anti-inflammatory effect in carrageen-induced paw edema in rats was significantly noted. Negative inotropic action on the isolated heart of frogs was noted. A vasodilative action in rabbits peripheral blood vessels and hypotension in anesthetized rabbits were remarkably recognized.