• Korean Journal of Veterinary Research
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• v.41 no.3
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• pp.311-317
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• 2001

In this work we have investigated the physiological effects of $MgCl_2$ in isolated atrium, papillary muscle, perfused heart and anesthesized guinea pig, The addition or infusion of $MgCl_2$ (0~20 mM or mg/kg) to perfused hearts and to anesthesized guinea pigs induced a marked and dose-dependent negative chronotropic effect. The sinoatrial node automaticity could also be reduced by $MgCl_2$. The addition of $MgCl_2$to isolated atria and to papillary muscles induced a marked and dose-dependent negative inotropic effect. The threshold voltage could be increased by $MgCl_2$in papillary muscle. Increasing $MgCl_2$ shortened the action potential duration (APD) in dose-dependent manner at 30% ($APD_{30}$) and 90% repolarization ($APD_{90}$) measured with conventional microelectrode technique in papillary muscle. In anesthesized guinea pig, the magnesium infusion resulted in a dose-dependent drop in blood pressure. These results suggested that magnesium is closely associated with cardiac physiological condition and exerts antiarrhythmic activities.

• Biomolecules & Therapeutics
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• v.5 no.4
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• pp.390-401
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• 1997

In order to investigate the pharmacological properties of New Woohwangchungsimwon Liquid (NCL), effects of Woohwangchungsimwon Liquid (CL) and NCL were compared. In isolated rat aorta, NCL and CL showed the relaxation of blood vessels in maximum contractile response to phenylephrine (10$^{-6}$ M) without regard to intact endothelium or denuded rings of the rat aorta. Furthermore, the presences of the inhibitor of NO synthase and guanylate cyclase did not affect the relaxation of NCL and CL. NCL and CL inhibited the vascular contractions induced by acetylcholine, prostaglandin endoperoxide or peroxide in a dose-dependent manner. In conscious spontaneously hypertensive rats (SHRs), NCL and CL significantly decreased heart rate. NCL and CL, at high doses, had a negative inotropic effect that was a decrease of LVDP and (-dp/dt)/(+dp/dt) in the isolated perfused rat hearts, and also decreased the contractile force and heart rate in the isolated rat right atria. In excised guinea-pig papillary muscle, NCL and CL had no effects on parameters of action potential at low doses, whereas inhibited the cardiac contractility at high doses. These results suggested that NCL and CL have weak cardiovascular effects with relaxation of blood vessels and decrease of heart rate, and that this effect is no significant differences between two preparations.

• Korean Journal of Veterinary Research
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• v.33 no.2
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• pp.199-209
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• 1993

The effects of ${\alpha}_1$-adrenergic stimulation on membrane potential, intracellular sodium activity $(a_N{^i{_a}})$, and contractility were investigated in the isolated papillary muscle of euthyroid, hyperthyroid, and hypothyroid guinea pigs. Cardiac alterations in the thyroid state have been shown to induce marked changes in action potential characteristics, the most pronounced shortening of action potential duration by hyperthyroidism and an increase in duration by hypothyroidism. $10^{-5}M$ Phenylephrine produced a decrease in $(a_N{^i{_a}})$ in euthyroid and hypothyroid preparations, but an increase in $(a_N{^i{_a}})$ in hyperthyroid ones. The major findings were that phenylephrine produced a stronger positive inotropic effect(PIE) without initial negative inotropic effect(NIE) in hyperthyroid preparations, while phenylephrine produced markedly NIE in hypothyroid ones. The alterations in membrane potential, $(a_N{^i{_a}})$, and contractility were abolished by $3{\times}10^{-5}M$ prazosin in hypothyroidism. In hypothyroid ventricular muscle, the decrease in $(a_N{^i{_a}})$ caused by phenylephrine were not abolished or reduced by $10^{-5}M$ strophanthidin, $10^{-5}M$ TTX, $3{\times}10^{-4}M$ lidocaine, or $100^{-5}M$ verapamil. These results indicate that the ${\alpha}_1$-adrenoceptor-mediated decrease in $(a_N{^i{_a}})$ is not associated with a stimulation of the $Na^+$-$K^+$ pump, inhibition of the $Na^+$ or $Ca^+$ channel in hypothyroid ventricular muscle. $10^{-5}M$ Phenylephrine decreased $(a_N{^i{_a}})$ but increased $(a_N{^i{_a}})$ in the presence of a PKC activator phorbol dibutyrate$(PDB_u)$. In conclusion, it is suggested that the following sequence of events in response to phenyleplhane occur in guinea pig ventricular muscle. First, changes in thyroid state may contribute to the ventacular electrophysiological propeties or ion transport system. Second, the adrenoceptor-mediated initial transient NIE may be associated with the decrease in $(a_N{^i{_a}})$ by PKC activation.

• Natural Product Sciences
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• v.5 no.1
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• pp.25-32
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• 1999

The pharmacological actions of ambrein were investigated alone or in combination as a pretreatment with agonists (adrenaline, noradrenaline, acetylcholine, histamine, nicotine), antagonists (atropine, atenolol) and calcium channel blocker (verapamil) in vivo in anaesthetized SWR rats using blood pressure, heart rate and myocardial contractility as parameters. Ambrein in the dose range of 50-200 mg/kg to the normotensive anaesthetized rats demonstrated negative chronotropic effect and increased the myocardial contractility significantly. At the mid dose (100 mg/kg) this increase in contractile force was 36% and 44% above the normal at 30 min and 60 min intervals post-treatment, respectively. Both of the lower and high doses (50 mg/kg and 200 mg/kg) had similar effects. Furthermore, this contractile response was dose related. Also, this compound produced a considerable increase in myocardial contractility when used as a pretreatment with some agonists and antagonists. The results on blood pressure did not show a considerable change when ambrein was used alone. However, ambrein pretreatment at the dose of 100 mg/kg did not block the effects of adrenaline, noradrenaline, isoprenaline and acetylcholine on heart rate and blood pressure. On the other hand, this pretreatment attenuated the sympathoadrenal effects of nicotine significantly. Chronotropic and blood pressure changes produced by histamine were also inhibited by ambrein pretreatment. This pretreatment significantly reversed the effects of atenolol but failed to demonstrate any change in the negative chronotropic, inotropic and hypotensive responses induced by verapamil. It is concluded that ambrein induced nonselective dose dependent antagonism of the effects of some agonists and antagonists require contribution of some neuromediators. However, the positive isotropic effects of ambrein possibly involve the enhancement of slow Ca channels and/or activation of ${\beta}-adrenergic$ receptors in the heart. At this moment it is difficult to explain the exact mode of action of ambrein and the studies dealing with Ca channel blocker and adrenergic blocker followed by ambrein may help to define the factors which contribute to its positive inotropic effects.

• The Korean Journal of Pharmacology
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• v.10 no.1 s.15
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• pp.55-59
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• 1974

Further elucidation of the mechanism of halothane's negative inotropic action has resulted from a study of the effect of various substrates on halothane-depressed rat atria. Approximately 6 mg% halothane was required to maintain a 50% depression of the contractility of rat atria suspended in a modified Krebs-Ringer bicarbonate glucose medium, pH 7.4, $30^{\circ}C$ for 2hr. Both lactate and acetate were found to restore partially the contractility of halothane-depressed atria. The maximally effective concentration of lactate was 5 mM; for acetate it was 2.5mM. Neither 5 nor 20 mM of additional glucose was effective in restoring the force of contraction of halothane-depressed atria. The results are consistent with the hypothesis that halothane exerts at least a part of its negative inotropic effect on rat atria by inhibiting either the uptake or utilization of glucose by the myocardium. The site of blockade must be prior to the conversion of pyruvate to acetyl CoA. In our previous report dealing with the mechanism of cardiac depressant action of inhalation anesthetic halothane, it has been demonstrated that: 1) approximately 6 mg/100 ml halothane is required to maintain 50% depression of the force of contraction of isolated rat atria in Krebs-Ringer bicarbonate glucose medium; 2) pyruvate partially restores the contractility of halothane-depressed atria, but has no effect on normal atria; the partial recovery of depressed atria by the addition of sodium pyruvate is due to the effect of the pyruvate ion itself, not to the sodium ion; 4) addition of pyruvate, to atria depressed with hypertonic medium, produced only further depression. From these findings we concluded that the cardiac depressant action of halothane on rat atria is a manifestation of inhibition of glucose uptake or utilization. The present studies were undertaken to observe the effect of other substrates on halothane-depressed atria in order to substantiate our conclusion. As with the case of pyruvate, lactate and acetate also partially restored the force of contraction of halothane-depressed atria. These data are consistent with the hypothesis that halothane inhibits glucose uptake or utilization in the glycolytic cycle of the myocardium.

• The Korean Journal of Pharmacology
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• v.13 no.2
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• pp.1-9
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• 1977

The effects of extracellular calcium concentrations and several concentration of Aconiti tuber butanol fraction, norepinephrine, ouabain on the force of isometric contraction of isolated atrial preparations obtained from rabbits were determined at $11{\sim}14$ different frequencies of contraction. Qualitatively similar results were obtained in all preparations. In most preparations, rested-state contraction was induced at the range of $120{\sim}400$ seconds stimulation interval. Over the range of intervals from 120 to 10 seconds negative inotropic effect of activation (NIEA) was predominant, so the steady-state contractile force progressively declined. At the intervals of 3 seconds, changes in the cumulated negative and positive isotropic effect of activation (PIEA) practically cancelled each other under steady-state conditions. At the interval from 3 seconds to 0.25 seconds, the additional cumulation of PIEA was greater than that of the NIEA. When the intervals between contractions were shorter than 0.25 seconds, the cumulation of the NIEA was again predominant. The positive inotropic effect of cardiac glycoside resulted at least in large part from increase in the rested-state contraction. No significant effect on the PIEA was found. The decay of the NIEA was apparently greatly accelerated in the presence of high concentration of ouabain, but this may also be a reflection of their action on the state determining the strength of the rested-state contraction. In the case of extracellular calcium concentration increment, the similar results with the ouabain treatment were obtained. Norepinephrine produced more powerful inotropic effect at shorter stimulation interval than long. The rested-state contraction and the decay of the NIEA were not significantly altered in the presence of norepinephrine, but cumulated PIEA and the amount of PIEA produced by each contraction were significantly increased. Aconiti tuber butanol fraction showed similar results with that of norepinephrine. The increment of contractile force at various contraction frequency were dose-responsive in the presence of Aconiti tuber butanol fraction. It is suggested that the positive inotropic effect of Aconiti tuber butanol fraction at various contraction frequency may be due to increase of the cumulation of PIEA and the amount of PIEA produced by each beat.

• YAKHAK HOEJI
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• v.28 no.5
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• pp.257-263
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• 1984

In our former report we observed that cinnarizine influenced the antihypertensive effect of propranolol beneficially, but not of metoprolol in SHR and normal cat. Cardiac contractilities and smooth muscle relaxations induced by above drugs were measured to elucidate their mechanism of action. In cinnarizine and propranolol treated group, both of negative inotropic and ${\beta}-blocking$ activity of propranolol in perfused rat hearts were increased and propranolol induced contraction in isolated arterial and trachea smooth muscle of the guinea pig was antagonized comparing to propranolol alone treated group. However, in the cinnarizine and metoprolol treated group, no significant differences in activity on the above were observed compared to metoprolol alone treated group.

• Journal of Chest Surgery
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• v.19 no.2
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• pp.197-208
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• 1986

Propranolol is one of clinically useful antiarrhythmic agents and electrophysiologically classified as group II. And the negative inotropic effect which is not related to adrenolytic effect has been demonstrated with high concentration of propranolol. On the other hand, it has been well known that the calcium plays a central role in excitation-contraction coupling process of myocardium and also in electrophysiological changes of cell membrane. Author studies the effect of propranolol on calcium uptake and release in sarcoplasmic reticulum and mitochondria prepared from porcine myocardium to investigate the mechanism of action of propranolol on myocardium. The results are summarized as follow: 1] The maximum Ca++-uptake of sarcoplasmic reticulum is inhibited by propranolol in a dose dependent manner. 2] The release of calcium from sarcoplasmic reticulum is not affected by propranolol but with higher than 1x10-3 M of propranolol, rate of calcium release from sarcoplasmic reticulum is decreased. 3] Propranolol inhibits the maximum uptake and uptake rate of calcium in mitochondria non-competitively. [Ki = 6.21 x 10-4 M] 4] The rate of Na+ induced calcium release from mitochondrion shows a function of [Na+]2 and is inhibited by propranolol with the concentration significantly lower than that affect the calcium uptake in sarcoplasmic reticulum and in mitochondria [Ki = 2.91 x 10-5 M]. These results suggest that propranolol affects the intracellular calcium homeostasis which may considered to be one of the mechanism of action of propranolol on myocardium.

• YAKHAK HOEJI
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• v.41 no.6
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• pp.802-816
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• 1997

In order to investigate the pharmacological properties of New Woohwangehungsimwon Pill (NWCH). Effects of Woohwangehungsimwon Pill (WCH) and NWCH were compared using various experimental models. In isolated rat aorta, NWCH and WCH showed the relaxation of blood vessels in maximum contractile response to phenylephrine ($10^{-6}$M) without regard to endothelium containing or denuded rings of the rat aorta. Furthermore, the presence of the inhibitors of NO synthase and guanylate cyclase did not affect significantly the relaxative effects of NWCH and WCH. NWCH and WCH inhibited the vascular contractions induced by acethylcholine, prostaglandin endoperoxide or peroxide in a dose-dependent manner. In conscious spontaneously hypertensive rats(SHRs), NWCH and WCH decreased significantly heart rate. These, at high doses, had a negative inotropic effect that was a decrease of LVDP and (-dp/dt)/(+dp/dt) in the isolated perfused rat hearts, and also decreased the contractile force and heart rate in the isolated rat right atria. In excised guinea-pig papillary muscle, these had no effects on parameters of action potential at low doses, whereas inhibited the cardiac, contractility at high doses. Furthermore, these had a significant inhibitory effects on heart acceleration in normotensive rats and SHRs. These results suggested that NWCH and WCH have weak cardiovascular effects, and that there is no significant differences between two preparations.

• Korean Journal of Veterinary Research
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• v.43 no.1
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• pp.31-39
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• 2003

We have investigated the effect of extracellular $Mg^{2+}$ ($[Mg^2+]_o$) on action potential duration (APD) in guinea pig papillary muscles by using microelectrodes. Increasing $[Mg^2+]_o$ resulted in progressive negative inotropic effect, progressive ascending depolarization of membrane potential, and increase in intracellular $Mg^{2+}$ concentration. In addition, increase in $[Mg^2+]_o$ from 1.1 to 3, 6, 10, and 20 mM produced a reversible dose-dependent shortening of both APD at 30% ($APD_{30}$) and 90% repolarization ($APD_{90}$), especially showing a tendency towards more remarkable prominent shortening in $APD_{30}$ than $APD_{90}$. Cooling from 37 to 33 and $27^{\circ}C$ diminished the $[Mg^2+]_o$-induced APD shortening. Increase in extracellular $Ca^{2+}$ concentration from 1.8 to 3.6 and 5.4 mM caused a significant depressed effect on the increasing $[Mg^2+]_o$-induced APD shortening. Furthermore, increase in $[Mg^2+]_o$ from 1.1 to 10 and 20 mM produced a significant depressed effect on the APD shortening induced by extracellular $Ca^{2+}$. Pretreatment of verapamil and imipramine significantly attenuated the increasing $[Mg^2+]_o$-induced APD shortening in both $APD_{30}$ and $APD_{90}$, whereas the $[Mg^2+]_o$-induced APD shortening was not affected by strophanthidin, glibenclamide and tetrabutylammonium. These findings suggest that the effects of $[Mg^2+]_o$ on APD are probably due to a decrease in ionic transport across plasma membrane. In conclusion, the present study indicates that $[Mg^2+]_o$ exerts antiarrhythmic activities by antagonistic actions on intracellular $Ca^{2+}$.