• The Korean Journal of Pharmacology
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• v.13 no.1 s.21
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• pp.7-12
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• 1977

Recently several reports have claimed that the bath temperature changes, such as lower bath temperature, produce supersensitivity on the positive chronotropic effect of catecholamine in cat, mouse and guinea pig atria. However, others showed controversial results against temperature-dependent supersensitivity. Similarly, the inotropic effect of ouabain is diminished in febrile state, however some investigators indicated that cardiac glycoside showed less toxicities and less effects in hypothermic condition. In this study, the effects of norepinephrine and epinephrine on inotropy and chronotropy in isolated rat atria was investigated by changing the temperature of bath ($30^{\circ}C$, $^35{\circ}C$ and $38^{\circ}C$). In addition, the effects of ouabain on atria in hypothermic bath was also studied. The followings are the results. 1. At the lower bath temperature isolated rat atrial rate was decreased and contractility was increased. 2. The chronotropic responses to norepinephrine and epinephrine in $38^{\circ}C$ were decreased when the bath temperature lowered to $35^{\circ}C$ or $30^{\circ}C$, while the inotropic responses were not affected. 3. Hypothermic supersensitivity to norepinephrine or epinephrine was not observed in rat atrium. 4. The inotropic response to ouabain was potentiated but chronotropic response was diminished by a lowering in the bath temperature. In conclusion, the chronotropic response of rat atrium to catecholamine was decreased, however, hypothermic supersensitivity was no longer present in rat atrium and the inotropic response of ouabain was increased at lower bath temperature.

• Korean Journal of Pharmacognosy
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• v.18 no.4
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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.

• Korean Journal of Pharmacognosy
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• v.17 no.4
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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.

• YAKHAK HOEJI
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• v.18 no.3
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• pp.165-182
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• 1974

• The Korean Journal of Pharmacology
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• v.32 no.2
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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.

• The Korean Journal of Physiology
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• v.14 no.2
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• pp.7-16
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• 1980

The effects of various inotropic interventions on the shape of the steady state length tension relation and the length-dependent activation process in cardiac muscle were studied. The influence of inotropic interventions upon the action potential was also observed. The range of varying muscle length was from the optimal length$(l_{max})$, where the active tension production is maximal, to 0.85 $l_{max}$. Changes in stimulus frequency or in external bathing Ca concentration constituted the inotropic interventions in this experiment. The papillary muscles were isolated from the rabbit right ventricles and perfused with $HCO-_3\;-buffered$ normal Tyrode solution which was aerated with $3%\;CO_2-97%\;O_2$ mixed gas and kept at $35^{\circ}C$. Resting Passive tension at $l_{max}$ was approximately 30% of the total tension and appeared from the muscle length of 0.90 $l_{max}$. The effect of stimulus frequency on the steady state level of developed tension was: As the stimulus frequency was increased from 0.1 to 0.5 Hz, there was little change in developed tension. As the frequency was increased further, to a value of about 3 Hz, tension increased steeply. Further increase of the frequency to 5 Hz had little additional effect on the developed tension. The length-tension curves for isometric peak tension became more steeper with the degree of potentiation by inotropic interventions. The relative steepness of the normalized length-tension curves where tension production was expressed as a percentage of maximal tension developed at $l_{max}$, varied inversely with the level of inotropic state and these curves were not superimposable one another. Thus at the stimulus frequency of 2 Hz or at the external Ca concentration of 8 mM, the relative decline in the developed tension for a given change in muscle length was considerably less than the decline observed at the frequency of 0.5 Hz or at the concentration of 2 mM Ca. Action potential duration was prolonged significantly as the frequency increased from 0.2 to 2 Hz, and this change in action potential duration was not observable on the changes in muscle length. There was a tendency of the hyperpolarization of membrane potential when the muscle length was shortened from $l_{max}$ to 0.95 $l_{max}$. These results support the hypothesis that there is a length-dependence of the activation process.

• The Korean Journal of Pharmacology
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• v.12 no.1
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• pp.45-55
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• 1976

The effect of positive inotropic agents on the contractile properties of myocardial muscle were studied in the cat papillary muscle preparation. For the purpose, the effects of ouabain $(1{\times}10^{-6}g/ml)$, norepinephrine (0.05r/m1) and Aconiti tuber butanol fraction (AF(5), $1{\times}10^{-4}$, $5{\times}10^{-4}$, $1{\times}10^{-3}$, $2{\times}10^{-3}g/ml$) on the contractile dynamics of the papillary muscle preparation isolated from right ventricle of cat were observed in terms of the characteristics of isometric twitch and the lengh-tension relation, the force-velocity relation and the load-extension relation of the series elastic component of contractile model of A.V. Hill. All the studied inotropic drugs similary increased the rate and the intensity of the developed isometric tension, while shortened the time from onset of contraction to peak tension and the total duration of contraction. In the afterloaded simultaneous isotonic and isometric contraction, they also similary increased the maximal velocity of shortening accompanied with the increasing the maximum developed force. In the load-extension relation all the drugs, however, had no appreciable influence on the properties of the series elastic component. Increasing the concentration, Aconiti tuber butanol fraction produced more pronounced effect on all the studied parameters of isometric and isotonic contraction of cat papillary muscle preparation. From the aspect of contractile dynamics, it seemed that the positive inotropic effect of ouabain, norepinephrine and Aconiti tuber butanol fraction are similary achieved through an influence on the behavior of the contractile component only.

• 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.

• 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.

• 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.