• 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.

• 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.

• The Korean Journal of Pharmacology
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• v.13 no.2
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• pp.11-17
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• 1977

The effects of varing concentrations of extracellular potassium on the positive inotropic actions of Aconiti tuber butanol fraction and ouabain were studied on isolated left atrium of rat. The patterns of active tension increment, such as time to peak and total duration of tension development, was contrasted in Aconiti tuber butanol fraction to ouabain. Ouabain did not induce significant shortening in time to peak and total duration of tension development, but Aconiti tuber produce significant shortening. The isometric tension and peak dF/dt were not significantly different at the range of extracellular potassium concentration $2mEq{\sim}10mEq$ per. liter in control studies. The ouabain-induced increase in active tension and peak dF/dt at 2mEq. per. liter potassium concentration was significantly different from that of 6mEq or 10mEq. per. liter, but there was no difference between 6mEq and 10mEq. per. liter. but Aconiti tuber is not. In contrast to ouabain, Aconiti tuber butanol fraction did not show potassium dependent positive inotropic effect. It produced almost same increment of tension and peak dF/dt at all the concentration of extracellular potassium concentrations in this experiment.

• 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 Circulation Journal
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• v.52 no.3
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• pp.173-197
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• 2022

Treatment options for patients with heart failure (HF) with reduced ejection fraction (HFrEF) have expanded considerably over the past few decades. Whereas neurohormonal modulation remains central to the management of patients with HFrEF, other pathways have been targeted with drugs that have novel mechanisms of action. The angiotensin receptor-neprilysin inhibitors (ARNIs) which enhance levels of compensatory molecules such as the natriuretic peptides while simultaneously providing angiotensin receptor blockade have emerged as the preferred strategy for inhibiting the renin angiotensin system. Sodium glucose cotransporter 2 (SGLT2) inhibitors which were developed as hypoglycemic agents have been shown to improve outcomes in patients with HF regardless of their diabetic status. These agents along with beta blockers and mineralocorticoid receptor antagonists are the core medical therapies for patients with HFrEF. Additional approaches using ivabradine to slow heart rate in patients with sinus rhythm, the hydralazine/isosorbide dinitrate combination to unload the heart, digoxin to provide inotropic support and vericiguat to augment cyclic guanosine monophosphate production have been shown in well-designed trials to have beneficial effects in the HFrEF population and are used as adjuncts to the core therapies in selected patients. This review provides an overview of the medical management of patients with HFrEF with focus on the major developments that have taken place in the field. It offers prospective of how these drugs should be employed in clinical practice and also a glimpse into some strategies that may prove to be useful in the future.

• 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 $Ca^{2+}$.

• The Korean Journal of Pharmacology
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• v.20 no.1 s.34
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• pp.55-65
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• 1984

Comparative effects of $PGF_{2{\alpha}}$ and ouabain on the isolated rat(Sprague-Dowley) atria were studied. The isolated rat atria were prepared for isometric myography in the isolated organ bath containing Feigen's solution perfused with 95% $O_2$ and 5% $CO_2$, and the pH of the medium was maintained at 7.4. The cumulative concentration-response relationship revealed the positive inotropic effects of both drugs with the higher potency of $PGF_{2{\alpha}}$ and the higher efficacy of ouabain. $PGF_{2{\alpha}}$ showed a positive chronotropic effect, but ouabain showed a tendency of increasing the contraction rate. In low-Ca(1.4 mM) medium, the positive inotropic and chronotropic effect of $PGF_{2{\alpha}}$(by $3{\times}10^{-8}M$) were preponderant $(p<0.05{\sim}p<0.005)$ over those of ouabain(by $3{\times}10^{-3}M$). $Ca^{++}$-addition(cumulative, to 2.8, 4.2, 5.6, and 7.0 mM) into the medium evoked the more sensitive response in the $PGF_{2{\alpha}}$ group than in the ouabain group. In low-K(2.8 mM) medium, the $PGF_{2{\alpha}}a(3{\times}10^{-8}M)$ group and the ouabain$(3{\times}10^{-3}M)$ group showed similar tensions(DT and RT) and contraction rates. And both group showed significantly(p<0.05p<0.01) higher tensions and contraction rates than those of the control group. By the cumulative addition of the $K^+$(to 4.2, 5.6, 7.0 and 8.4 mM), only the DT of the $PGF_{2{\alpha}}$ group was sustained at signifcantly$(p<0.05{\sim}p<0.01)$ higher level than the DT of the control group. The $K^+$-addition inhibited the positive inotropic effect of ouabain significantly (p<0.05). The cumulative addition of lidocaine in high concentrations $(1{\times}10^{-5}\;to\;1{\times}10^{-3}M)$ evoked no significant influence on the intropic activities of $PGF_{2{\alpha}}$ and ouabain, but significant ${\beta}$-blockade with propranolol could not inhibit the positive intropic and chronotropic effect of $PGF_{2{\alpha}}$. In conclusion, it is presumed that $PGF_{2{\alpha}}$ may have some more active mechanism of accelerating the influx of $Ca^{++}$ across the cell membrane of the isolated rat atria as compared with ouabain, and the action site may be located at the cell membrane. As a supposition which needs further investigations, it is presumed that $PGF_{2{\alpha}}$ may have its specific membrane receptors on the atrial muscle or sinus node cells.

• The Korean Journal of Pharmacology
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• v.28 no.1
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• pp.41-48
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• 1992

A concentration of 0.01 mM bupivacaine was necessary to maintain approximately 50% depression of contractility of rat atria suspended in a modified Krebs-Ringer bicarbonate glucose medium, pH 7.4 at $30^{\circ}C$. Sodium pyruvate, sodium acetate, and fructose partially restored the contractility of the bupivacaine-depressed atria. However, 20 mM glucose had no effect on the bupivacaine-depressed atria, although this concentration of glucose markedly increased the contractility of normal atria not to be exposed to bupivacaine. Contractility of normal atria was not significantly influenced by sodium pyruvate, sodium acetate, and fructose. The results suggested that at least part of the negative inotropic action of bupivacaine is the result of inhibition of glucose uptake or utilization in the glycolytic pathway, and further pinpoint the blockade as an early step in the glycolytic sequence prior to the phosphofructokinase step.

• Korean Journal of Pharmacognosy
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• v.13 no.4
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• pp.137-144
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• 1982

It was previously reported from our laboratory that the rate of deterioration of the force of contraction was slower in heart from Panax ginseng extract treated rats. The study carried out to elucidate its mechanism of the action on hearts. The cyclic AMP content in the rat hearts was measured by the method of radioimmunoassay techniques. Panax ginseng extract (100mg/kg/day) was administered orally to male Sprague-Dawley rats weighing 150g to 250g for 1 week and after 24 hrs the hearts were isolated and the cyclic AMP content in the fresh heart was assayed. The difference in cyclic AMP content between the rats treated with Panax ginseng extracts and normal rats was not significant. Panax ginseng extract(l00mg/kg/day) was administered orally to the rats for I week and after 24 hrs the hearts were isolated and perfused with Krebs-Henseleit buffer (pH7.4) for 90min. The cyclic AMP content in the both treated and normal rats was not also significantly different. On the other hand, when total ginseng saponin (50mg/kg/day) was administered orally to rats for 1 week and after 24 hrs, the isolated hearts were perfused with Krebs Henseleit solution for 32min, the cyclic AMP content in total ginseng soponin treated hearts was decreased by 18.7% compared to normal rats. It was also observed that when isolated hearts were perfused with total ginseng saponin $(10^{-4}g/ml)$ for 12 min after 30 min equilibration period, the cyclic AMP content in total ginseng saponin treated hearts was decreased by 23.7% compared to normal rats. Isolated hearts were perfused with ginseng saponins $(10^{-4}g/ml)$ or with Krebs-Henseleit solution alone for 10min and subsequently with dl-isoproterenol $(1/2{\times}10^{-6}M)$ until the positive inotropic effect of isoproterenol was initiated. The cyclic AMP content in each rat hearts treated with total ginseng saponin, or with ginsenoside $Rb_1$, or with Krebs-Henseleit solution alone were increased by 35.5%, 42.4%, 47.5%, respectively, compared to normal rats.

• Korean Journal of Veterinary Research
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• v.32 no.1
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• pp.41-49
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• 1992

Higenamine is an Aconiti tuber derived compound whose chemical structure is 1-(4'-hydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline containing catechol ring and tetrahydroisoquinoline nucleus in its own structure, both of which are well known to have agonistic effects on adrenergic receptors. Using guinea-pig atria(rich in ${\beta}_1$-receptor) and treachea(rich in ${\beta}_2$-receptor), we studied pharmacological actions of higenamine on these organs with special interest of its relevancy of ${\beta}$-receptor selectivity. In order to further clarify its pharmacological characteristics, the influncences of pretreatment of reserpine or cocaine were also investigated. The results were summarized as follows : 1. Higenamine had remarkable chronotropic, inotropic and bronchodilator effects in guinea-pig spontaneously beating right atria, left atria and trachea, in dose-dependent manners. 2. All of above actions were blocked competitively by propranolol, which shows nonselectivity of higenamine on ${\beta}$-receptor. $pA_2$ values of propranolol against higenamine were 7.93, 7.76 and 8.46 in guinea-pig right atria, left atria and treachea, respectively. 3. Reserpine pretreatment(5mg/kg, ip, 24h) did not show my decrease in pharmacological actions of higenamine, which suggests higenamine has direct action on ${\beta}$-receptor not via catecholamine release. 4. Cocaine pretreatment$(1{\mu}M)$ had no influence on pharmacological actions of higenamine in contrast with nor epinephrine, which suggests there is no neuronal uptake mechanism of higenamine in the studied organ preparations.