• CELLMED
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• v.2 no.3
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• pp.21.1-21.8
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• 2012

Heart disease that ultimately leads to heart failure (HF) has been the number one cause of death in the United States as well as in many other countries for over a century. Inotropic therapy utilizing cardiotonics to increase cardiac contractility remains a significant component of the management of HF. However, adverse effects of currently available cardiotonics have been compromising their therapeutic value and often lead to further myocardial dysfunction. Thus, discovery of safe cardiotonics remains a main challenge to improvement of inotropic therapy for HF. This review briefly summarized cellular mechanisms underlying the inotropic action of currently available cardiotonics, newly-developed carditonics and the bark of Terminalia arjuna (TA), a tropical tree used in ayurvedic medicine. The potential of TA bark as a new cardiotonic in inotropic treatment for HF was also discussed.

• YAKHAK HOEJI
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• v.32 no.2
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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.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.3
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• pp.730-734
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• 2006

Aqueous extracts of medicinal plants traditionally used in the East Asia such as China, Korea, and Japan were screened for inotropic activity using isolated rabbit atria. Among the twenty-one aqueous-extracts from medicinal plants, the aqueous extracts of Convallaria keiskei(ACK) and rhizome of Coptis chinesis (ACC) were found to exhibit distinctive positive inotropic activity. The aqueous extracts of C. keiskei and rhizome of C. chinensis significantly increased atrial stroke volume and pulse pressure in beating rabbit atria. These findings suggest that the aqueous extracts of C. keiskei and rhizome of C. chinensis enhance the cardiac muscle contractility and then could be useful for the treatment of cardiac failure.

• The Korean Journal of Physiology
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• v.20 no.2
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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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• 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.

• 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$_{1}$.

• 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.

• 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 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.

• Journal of Physiology & Pathology in Korean Medicine
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• v.30 no.1
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• pp.40-46
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• 2016

Many medicinal plants have been used for the treatment of edema, jaundice, and gonorrhea in traditional Oriental medicine. This screening study was designed to search the positive inotropic effects of herbal extracts in beating rabbit atria. Aquarius extracts of twenty six herbs were examined in atrial mechanical dynamics such as pulse pressure and stroke volume and atrial natriuretic peptide (ANP), one of the main hormones involved in the regulation of the body fluid and blood pressure homeostasis in perfused beating rabbit atria. Sophora flavescens Ait., Rheum officinale Baill., Acorus gramineus Sol., Chelidonium majus L., Pulsatilla koreana Nakai., Reynoutria japonica Houtt., Euphorbia lathyris L., Pyrrosia lingua (Thunb.) Farwell, Poncirus trifoliata Rafin., Anemarrhena asphodeloides Bunge, Kochia scoparia Schrad. significantly increased stroke volume and pulse pressure. However, those herbal extracts were not induced ANP secretion. We clarified the eleven herbal extracts for the positive inotropic effect independent of ANP secretion in beating rabbit atria. Thus these results provide a beneficial data for the treatment of the impairment of body fluid and blood pressure in traditional Oriental medicine.