• The Korean Journal of Pharmacology
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• v.2 no.1 s.2
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• pp.21-29
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• 1966

Dichloroisoproterenol(DCI) i; one of the well known ${\beta}$-adrenergic receptor blocking agents. According to Moran and Perkins, DCI has sympathomimetic like action in relatively low concentrations. Fleming and Hawkins confirmed that DCI acts upon the receptors concerned with positive chronotropic and inotropic actions in the heart. Vogins reported that DCI, in concentration of $5{\times}10^{-8}$ to $5{\times}10^{-6}g/ml$, had properties of sympathomimetic amine causing positive inotropic and chronotropic actions in normal rat atria. And James and Nadeau found that DCI had not only adrenergic blocking effect in moderate and higher concentrations, but it also blocked the effect on the sinus node by vagal stimulation and of directly administered acetylcholine in higher concentrations. As stated above by many authors, DCI has complicated actions according to its concentrations. Our aim at the present experiments was to study the effects of DCI to the action of ouabain and acetylcholine upon the excised rabbit atria, as well as to the action of barium chloride and acetylcholine upon the excised rabbit intestine. In addition, Pan ax Ginseng is widely used as tonics in oriental nations, its pharmacological action, however, has not been clearly established. So we atempted to investigate the effects of the water extract of Panax Ginseng to the action of ouabain and DCI upon both atria and intestine. The results obtained were as follows. 1) DCI has a negative inotropic effect on the excised rabbit atria at concentration of $10^{-5}$ and a positive inotropic effect at concentration of $10^{-6}$. 2) DCI (at concentration of $10^{-6}$) potentiates the positive inotropic effect of ouabain upon the excised rabbit atria. 3) DCI antagonizes the action of acetylcholine upon the excised rabbit atria. 4) The water extract of Panax Ginseng, at concentration of $10^{-3}$, decreases the contractile force of rabbit atria, and tends to slightly increase that of rabbit atria at $10^{-4}$. 5) The water extract of Panax Ginseng exhibits a synergistic action with ouabain on the contractile force of rabbit atria. 6) DCI, in concentrations of $10^{-7}{\sim}10^{-6}$, depresses the tone and amplitude of contraction of the excised rabbit intestine. The depression of the intestinal tone markedly appears in pretreatment with reserpine 2mg/kg 24 hours. 7) DCI antagonizes the contractile effect of barium chloride on the excised rabbit atria. 8) DCI has no significant influence on the action of acetylcholine upon the excised rabbit intestine. 9) The series of those evidences indicates that DCI has a sympathomimetic-like action and more over a relaxing action directly on the excised rabbit intestine. 10) The water extract of Panax Ginseng in concentrations of $10^{-4}{\sim}10^{-3}$, has transient depression of the intestinal tone, but later gradually recovers its normal motility: 11) The water extract of Panax Ginseng has a synergistic action with ouabain on the intestinal contractility.

• YAKHAK HOEJI
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• v.24 no.1
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• pp.15-25
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• 1980

The investigation is concerned with the action of ginseng saponin on the contractile force in the rat heart and with the elucidation of the mechanism of the action. The effect of total ginseng saponin, ginsenoside Rb$_{1}$ of protopanaxadiol derivatives and ginsenoside Re of protopanaxatriol derivatives on the contractile force in isolated spontaneously beating normal rat heart was investigated. Total ginseng saponin was obtained from white ginseng by the method of Shibata and Namba. Ginsenoside Rb$_{1}$ and ginsenoside Re were isolated by the method of and Han, respectively. Total ginseng saponin exhibited a slight increase of the contractile force. Ginsenoside Rb$_{1}$ increased markedly the contractile force and dose dependent increase in contractile force was observed. However, ginsenoside Re did not increase the contractile force, but it prevented spontaneous decrease of the contractility of the heart. The mixture of the same dose of ginsenoside Rb$_{1}$ and Re showed a slight increase in the contractile force and its effect was similar to that obtained by total ginseng saponin. Pretreatment with propranolol abolished the positive inotropic effect of ginsenoside Rb$_{1}$ and the positive inotropic effect of ginsenoside Rb$_{1}$ was not observed in a reserpinized rat heart. Pretreatment with ginsenoside Re decreased or abolished the positive inotropic effect of epinephrine. Activities of Na+, K+ -ATPase were inhibited by ginsenoside Rb$_{1}$, total ginseng saponin and ginsenoside Re and these inhibitory effects were dose dependent. The results suggest that catecholamine release or inhibition of Na+, K+ -ATPase activities may be involved in the positive inotropic effect of gindenoside Rb$_{1}$. Ginsenoside Re counteracted the positive inotropic effect of ginsenoside Rb$_{1}$.

• YAKHAK HOEJI
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• v.32 no.6
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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.

• The Korean Journal of Pharmacology
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• v.22 no.1 s.38
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• pp.1-23
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• 1986

• The Korean Journal of Physiology
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• v.29 no.2
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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.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1995.04a
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• pp.88-88
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• 1995

Tetrahydroisoquinoline (THI) compounds have various pharmacological actions in the cardiovascular system. Recently, we have synthesized 1-${\alpha}$-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, YS 49. In the present study, we evaluated the effect of YS-49 on positive inotropic and chronotropic action using isolated rat heart and on blood pressure and heart rate using anesthesized rabbit. Vasodilating action was also assessed in isolated rat thoracic aorta. YS 49, concentration-dependently relaxed rat aorta precontracted with phenylephrine (PE, 0.3 ${\mu}$M) and high potassium (high K$\^$+/, 65.4 mM). The 50% inhibitory concentration (IC$\sub$50/) of YS 49 in PE-induced and high K$\^$+/-induded contraction was 5.36 ${\mu}$M and 2.52 ${\mu}$M, respectively. In isolated rat atria, YS 49 increased both heart rate and force, and in anesthesized rabbit it decreased blood pressure but increased heart rate. In addition, to know the mechanism of action of the compound, propranolol, nonselective ${\beta}$-antagonist, and phentolamine, ${\alpha}$-blocker, were used. Furthermore, a comparison with the effect of higenamine, trimetoquinol on the vasodilating action in rat thoracic aorta was also made. The action of YS 49 was inhibited by the presence of propranolo, not pentolamine. These results indicate that cardiotonic and vasodilatory action of YS 49 is attributable, at least in part, for ${\beta}$-receptor stimulation.

• The Korean Journal of Pharmacology
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• v.17 no.2
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• pp.7-16
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• 1981

Higenamine ($Ca_{26}H_{17}No_3$. HCI, d1-1- (4-hydroxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline hydrochloride), which has recently teen isolated from the Aconite root, was known to the cardiotonic component of the Aconite root. The positive inotropic effect of Higenamine was observed in the isolated electrically driven left atrium from rabbits with respect to the influences of extracellular calcium and of calcium antagonists, e.g. $La^{+++}$ and verapamil. A synergistic relation in the positive inotropic effect could be demonstrated between Higenamine and extra cellular calcium. The inotropic potency of $10^{-7}\;g/ml$ Higenamine was equivalant to that of 0.058 mM of calcium in the medium. In the preparation, of which contractility had been reduced by the treatment of $La^{+++}(10^{-5}-10^{-4}M)$ and verapamil$(2{\times}10^{-7}-10^{-6}M)$, Higenamine was able to restore the contractility. These results indicated that one of the possible mechanism of positive inotropism of Higenamine was to accelerate the influx of calcium from the extracellular space through the sarcolemma.

• YAKHAK HOEJI
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• v.55 no.2
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• pp.168-171
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• 2011

Chrysosplenol C [5,6-dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxychromen-4-one] is a flavonoid found in Miliusa balansae and Pterocaulon sphacelatum. We have recently shown that chrysosplenol C has positive inotropic effect in isolated rat ventricular myocytes. In the present study, we explored a possible mechanism for the positive inotropic effect of chrysosplenol C by examining intracellular $Ca^{2+}$ transients during action potentials. The intracellular $Ca^{2+}$ transients were measured by confocal $Ca^{2+}$ imaging in field-stimulated single rat ventricular myocytes. Chrysosplenol C (50 ${\mu}M$) significantly increased the magnitudes (${\Delta}F/F_0$) of $Ca^{2+}$ transients (control, $1.08{\pm}0.05$; chrysosplenol C, $1.25{\pm}0.03$; n=8, P<0.01). Half decay time of the action potential-induced $Ca^{2+}$ transient was not altered by chrysosplenol C (50 ${\mu}M$) (control, $154{\pm}6$ ms; chrysosplenol C, $167{\pm}11$ ms; n=21). The $Ca^{2+}$ content in the sarcoplasmic reticulum (SR), measured as caffeine (10 mM)-induced $Ca^{2+}$ transient, was significantly decreased by chrysosplenol C (50 ${\mu}M$). These results indicate that chrysosplenol C increases $Ca^{2+}$ transients without altering $Ca^{2+}$ removal kinetics in ventricular myocytes, providing a possible mechanism for its positive inotropic effect.

• The Korean Journal of Pharmacology
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• v.19 no.2
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• pp.9-16
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• 1983

The effect of higenamine upon the interval-strength relationship was kinetically analyzed, and compared them with epinephrine and calcium ion. The followings are result obtained : 1) Polyphasic patterns were seen by all agents applied on the interval-force curve of rabbit atrial muscle. 2) Higenamine, unlike calcium ion, increased the amount of PIEA produced per beat dose-dependently and scarcely affected the disappearance of NIEA. 3) Higenamine appeared to similar pattern with epinephrine in augmenting the PIEA, not affecting the NIEA. 4) Calcium ion slightly influenced the PIEA, rather hastened the disappearance of NIEA. From these result the positive inotropic action of higenamine was attributed solely to increment of PIEA.

• The Korean Journal of Pharmacology
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• v.17 no.1 s.28
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• pp.9-15
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• 1981

Aconiti tuber butanol fraction, which is isolated from the chloroform insoluble and water soluble extract of Aconitum volubile, has been recently known to have a potent positive inotropic effect in the isolated cardiac muscle preparations of various animals. The positive inotropic mechanism of Aconiti tuber butanol fraction, in relation with the external calcium, was studied using the isolated cat papillary muscle. The positive inotropic effect was dependent on the calcium concentration in the nutrient medium, and a synergistic relation could be demonstrated between Aconiti tuber butanol fraction and the external calcium. The inotropic effect of $10^{-4}g/ml$ of Aconiti tuber butanol fraction was equivalent to that of 0.06mM of calcium in the medium. After the treatment with a calcium influx inhibitor, Verapamil$(2{\pm}10^{-7}-10^{-6}M)$, the contractile force of the papillary muscle was markedly inhibited. In these preparations, Aconiti tuber butanol fraction restored the decreased contractility in a dose-dependent manner. It was suggested that the positive inotropic effect of Aconiti tuber butanol fraction might be related with the stimulating action on the calcium influx through the slow inward calcium channels in the cardiac cell membrane. In contrast with digitalis cardiac glycoside, Aconiti tuber butanol fraction infused intravenously into the anesthetized rabbit decreased the systemic arterial blood pressure and increased the carotid blood flow, but produced no prominent changes in the heart rate.