• 대한약침학회지
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• 제25권4호
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• pp.369-381
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• 2022

Objectives: Hyperlipidemia (HL) is a major cause of ischemic heart diseases. The size-limiting effect of ischemic preconditioning (IPC), a cardioprotective phenomenon, is reduced in HL, possibly because of the opening of the mitochondrial permeability transition pore (MPTP). The objective of this study is to see what effect pretreatment with Inula racemose Hook root extract (IrA) had on IPC-mediated cardioprotection on HL Wistar rat hearts. An isolated rat heart was mounted on the Langendorff heart array, and then ischemia reperfusion (I/R) and IPC cycles were performed. Atractyloside (Atr) is an MPTP opener. Methods: The animals were divided into ten groups, each consisting of six rats (n = 6), to investigate the modulation of I. racemosa Hook extract on cardioprotection by IPC in HL hearts: Sham control, I/R Control, IPC control, I/R + HL, I/R + IrA + HL, IPC + HL, IPC + NS + HL, IPC + IrA+ HL, IPC + Atr + oxidative stress, mitochondrial function, integrity, and hemodynamic parameters are evaluated for each group. Results: The present experimental data show that pretreatment with IrA reduced the LDH, CK-MB, size of myocardial infarction, content of cardiac collagen, and ventricular fibrillation in all groups of HL rat hearts. This pretreatment also reduced the oxidative stress and mitochondrial dysfunction. Inhibition of MPTP opening by Atr diminished the effect of IrA on IPC-mediated cardioprotection in HL rats. Conclusion: The study findings indicate that pretreatment with IrA e restores IPC-mediated cardioprotection in HL rats by inhibiting the MPTP opening.

• Biomolecules & Therapeutics
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• 제7권4호
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• pp.354-361
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• 1999

In this study, the effects of tauroursodeoxycholic acid (TUDCA) on ischemia/ reperfusion injury were investigated on isolated heart perfusion models. Hezrts were perfused with oxygenated Krebs-henseleit solution (pH 7.4, $37^{\cire}C$) on a Langendorff apparatus. After equilibration, isolated hearts were treated with TUDCA 100 and 200 $\mu\textrm{M}$ or vehicle (0.02% DMSO) for 10 min before the onset of ischemia in single treatment group. In 7 day pretreatment group. TUDCA 50, 100 and 200 mg/kg body weight were given orally for 7 days before operation. After global ischemia (30 min), ischemic hearts were reperfused for 30 min. The physiological (i.e. heart rate, left ventricdular developed pressure, coronary flow, double product, time to contracture formation) and biochemical (lactate dehydrogenase; LDH) parameters were evaluated. In vehicle-treated group, time to contracture formation was 810 sec during ischemia, LVDP was 34.0 mmHg at the endpoint of reperfusion and LDH activity in total reperfusion effluent was 34.3 U/L. Single treatment with TUDCA did not change the postischemic recovery of cardiac function, LDH and time to contractur compared with ischemic control group. TUDCA pretreatment showed the tendency to decrease LDH release and to increase time to contracture and coronary flow. Our findings suggest that TUDCA does not ameliorate ischemia/reperfusion-reduced myocardial damage.

• The Korean Journal of Physiology and Pharmacology
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• 제10권4호
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• pp.181-186
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• 2006

This study was undertaken to evaluate whether peroxisome proliferator-activated-receptor-gamma $(PPAR-{\gamma})$ agonist-rosiglitazone (ROSI) induces postischemic functional recovery in Langendorf heart model. Hearts isolated from normal rats were subjected to 20 min of normoxia or 25 min zero-flow ischemia followed by 50 min reperfusion. In this acute protocol, ROSI $(20\;{\mu}g/ml)$ administered 10 min before ischemia had no effect on hemodynamic cardiac function, but had protective effect on lipid peroxidation in in vitro experiments. In chronic protocol in which ROSI was given by daily gavage (4 mg/kg) for three consecutive days, ROSI could not prevent the hemodynamic alteration on cardiac performance, but has protective effect on the activity of superoxide dismutase (SOD). There was no significant difference in the contents of reduced glutathione (GSH) and catalase activity between ischemia-reperfusion (IR) and ROSI treated IR hearts. Although ROSI had no effect on hemodynamic factor, it had effect on antioxidant activity. Our results indicate that ROSI provides partial beneficial effects by inhibiting lipid peroxidation and/or recovering normal level of SOD activity in the ischemic reperfused heart.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1998년도 Proceedings of UNESCO-internetwork Cooperative Regional Seminar and Workshop on Bioassay Guided Isolation of Bioactive Substances from Natural Products and Microbial Products
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• pp.199-199
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• 1998

In this study, the effects of ursodeoxycholic acid (UDCA) on ischemia/reperfusion injury were investigated on retrograded aortic perfusion model. Hearts from Sprague-Dawley rats were perfused with oxygenated Krebs-Henseleit solution (pH 7.4, 37) on a Langendorff apparatus. After equilibration, hearts were treated with ursodeoxycholic acid 10, 20, 40 and 800 M or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. Following 25 min of global ischemia, ischemic hearts were reperfused and allowed to recover for 30 min. The physiological (i.e. heart rate, left ventricular diastolic pressure, coronary flow and time to contracture formation) and biochemical (lactate dehydrogenase, LDH) endpoints were evaluated. In vehicle group, time to contracture formation (TTC) value was 19.5 min during ischemia, LVDP was 20.8 mmHg at the endpoint of reperfusion and LDH activity in reperfusate was 59.7 U/L. Cardioprotective effects of UDCA following ischemia/reperfusion consisted of a reduced TTC (EC$\_$25/ = 16.10 M), reduced LDH release and enhanced recovery of contractile function during reperfusion. Especially, the treatments of UDCA 80 M remarkably increased LVDP (68.1 mmHg) and reduced LDH release (33.2 U/L). Our findings suggest that UDCA ameliorates ischemia/reperfusion-induced myocardial damage, in agreement with physiological and biochemical parameters.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.749-758
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• 1997

Myocardial ischemia-reperfusion injury is known to be mediated by reactive oxygen species. The myocardial cell is equipped with endogenous antioxidant defensive system which can be adaptively stimulated by various oxidative stress. It is postulated that an increased oxygen partial pressure induced by hyperbaric oxygenation impose an oxidative stress on the cells, resulting alterations in the endogenous antioxidant system. In this study we investigated the effect of hyperbaric oxygenation on the activities of myocardial antioxidant enzymes and observed whether the hyperbaric oxygenation could protect the ischemia-reperfusion injury of heart. Rats or rabbits were pretreated with hyperbaric $oxygenation(2{\sim}3\;atm\;O_2/1{\sim}3\;hrs/1{\sim}10\;days)$. The changes in activities of major antioxidant enzymes(superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phasphate dehydrogenase), functional recovery and infarct size were observed in the experimentally induced ischemia-reperfused hearts. In the hearts isolated from rats pretreated with $2\;atm\;O_2/1{\sim}2\;hrs$ for 5 days, the functional recovery after reperfusion(20 min) following global ischemia(25 min) was significantly increased without any observable oxygen toxicity. Lactate dehydrogenase release was also significantly reduced in this hyperbaric oxygenated rat hearts. In in vivo regional ischemia(30 min) model of rabbit hearts, pretreatrment with $2\;atm\;O_2/1\;hr$ for 5 days significantly limited the infarct size. Among the myocardial antioxidant enzymes of rat hearts pretreated with the hyperbaric oxygenation, the activities of catalase, superoxide dismutase and glucose-6-phosphatase dehydrogenase were increased, while those of glutathione peroxidase and reductase were not changed. There were lethal cases in the groups of rats exposed to 3 atm $3\;atm\;O_2/2{\sim}3\;hrs$ for 5 days. A lipid-peroxidation product, rnnlondialdehyde was increased in brains and livers of the rats exposed to$2\;atm\;O_2/2{\sim}3\;hrs/5\;days\;and\;3\;atm\;O_2/1\;hr/5days$. The present results suggest that the pretreatment of hyperbaric oxygenation can protect the post-ischemic rererfused hearts in association with a stimulation of the activities of myocardial antioxidant defensive enzymes, and that the hyperbaric oxygenation of $2\;atm\;O_2/1\;hr$for 5 days would be a safe condition which does not produce any oxygen toxicity.

• The Korean Journal of Physiology and Pharmacology
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• 제4권6호
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• pp.515-523
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• 2000

Polymorphonuclear leukocytes (PMNs) play an important role in myocardial ischemia/reperfusion (MI/R) injury. Moreover, platelets are also important blood cells that can aggravate myocardial ischemic injury. This study was designed to test the effects of PMNs and platelets separately and together in provoking cardiac dysfunction in isolated perfused rat hearts following ischemia and reperfusion. Additional control rat hearts were perfused with $75{\times}10^6$ PMNs, with $75{\times}10^6$ platelets, or with $75{\times}10^6\;PMNs+75{\times}10^6$ platelets over a five minute perfusion followed by a 75 min observation period. No significant reduction in coronary flow (CF), left ventricular developed pressure (LVDP), or the first derivative of LVDP (dP/dt max) was observed at the end of the observation period in any non-ischemic group. Similarly, global ischemia (I) for 20 min followed by 45 minutes of reperfusion (R) produced no sustained effects on the final recovery of any of these parameters in any group of hearts perfused in the absence of blood cells. However, I/R hearts perfused with either PMNs or platelets alone exhibited decreases in these variables of $5{\sim}10%$ (p＜0.05 from control). Furthermore, I/R hearts perfused with both PMNs and platelets exhibited decreases of 50 to 60% in all measurements of cardiac function (p＜0.01). These dual cell perfused I/R hearts also exhibited marked increases in cardiac myeloperoxidase (MPO) activity indicating a significant PMN infiltration, and enhanced P-selectin expression on the coronary microvascular endothelium. All cardiaodynamic effects as well as PMN accumulation and P-selectin expression were markedly attenuated by a recombinant soluble PSGL-1 which inhibits selectin mediated cell adhesion. These results provide evidence that platelets and PMNs act synergistically in provoking post-reperfusion cardiac dysfunction, and that this may be largely due to cell to cell interactions mediated by P-selectin. These results also demonstrate that a recombinant soluble PSGL-1 reduces myocardial reperfusion injury by platelet and PMNs interaction.

• The Korean Journal of Physiology and Pharmacology
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• 제8권1호
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• pp.43-50
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• 2004

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in a marked cardiac contractile dysfunction. Amrinone, a specific inhibitor of phosphodiesterase 3, has an antioxidant activity against PMNs. Therefore, we hypothesized that amrinone could attenuate PMNs-Induced cardiac dysfunction by suppression of reactive oxygen species (ROS) produced fby PMNs. In the present study, we examined the effects of amrinone on isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Amrinone at $25\;{\mu}M$, given to hearts during the first 5 min of reperfusion, significantly improved coronary flow, left ventricular developed pressure (P<0.001), and the maximal rate of development of left ventricular developed pressure (P<0.001), compared with ischemic/reperfused hearts perfused with PMNs in the absence of amrinone. In addition, amrinone significantly reduced myeloperoxidase activity by 50.8%, indicating decreased PMNs infiltration (p< 0.001). Superoxide radical and hydrogen peroxide production were also significantly reduced in fMLP- and PMA-stimulated PMNs pretreated with amrinone. Hydroxyl radical was scavenged by amrinone. fMLP-induced elevation of $[Ca^{2+}]_i$ was also inhibited by amrinone. These results provide evidence that amrinone can significantly attenuate PMN-induced cardiac contractile dysfunction in the ischemic/reperfused rat heart via attenuation of PMNs infiltration into the myocardium and suppression of ROS release by PMNs.

• Journal of Chest Surgery
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• 제36권11호
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• pp.799-811
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• 2003

배경: 본 연구에서는 심정지액 중 비교적 최근에 임상에 소개된 HTK 심정지액과 DelNido 심정지액의 심근보호효과를 비교하고자 하였다. 이를 위하여 적출 쥐의 심장을 사용한 동물실험을 통하여 혈류역학적 심기능검사, 생화학적 대사물질검사 및 심근미세구조의 변화를 비교 관찰하여 그 성적을 보고하는 바이다. 대상 및 방법: 심정지액 투여방법을 기준으로 흰쥐 수컷 79마리를 세 군으로 나누어서 실험하였다. 제1군(28마리)에서는 DelNido 심정지액을 1차 주입 후 40분 간격으로 2차, 3차 주입을 하였고, 제2군(27마리)에서는 HTK 심정지액을 1차례만 주입하였으며, 제3군(24마리)에서는 HTK 심정지액을 DeINido 심정지액과 같은 방법으로 3차례 주입하였다. 혈류역학적 심기능검사로 심박동수, 좌심실내압, 심근수축력(+dp/dt max), 분당 관 관류량 및 심부담값을 각 군에서 허혈전과 재관류후 15분, 30분 및 45분에 측정하여 비교하였다. 생화학적 대사물질검사로는 aspartate aminotransferase (AST), lactate dehydrogenase (LD), creatine kinase (CK), creatine kinase-MB (CK-MB), troponin-I, myoglobin, lactate를 허혈 전과 재관류 45분 후에 관 관류액을 취하여 측정하였다. 심근미세구조검사는 혈류역학적 심기능검사에서 비교적 중간값을 보인 실험 3예에서 재관류 45분 후 심첨부에서 좌심실 심근의 일부를 생검하여 전자현미경으로 관찰하였다. 결과: 혈류역학적 심기능검사상 재관류 후 좌심실 내압, 분당 관 관류량, 심부담값의 감소율 비교 시 통계학적 유의성은 없었으나, 재관류 후 심박동수의 감소율이 대조군(제1군)보다 실험군(제2군과 제3군)에서 유의하게 낮았다. 생화학적 대사물질 검사상 재관류 후 AST, LD, CK, CK-MB, troponin-I, myoglobin의 증가율 비교 시 통계학적 유의성은 없었으나, 재관류 후 lactate치의 증가율이 대조군보다 실험군에서 유의하게 낮았다 심근미세구조검사상 제1군, 제2군, 제3군에서 사립체 점수는 2.14$\pm$0.10, 1.52$\pm$0.57, 2.10$\pm$0.16으로 관찰되었다. 결론: 이상의 흰쥐의 적출심장을 이용한 실험결과를 종합해보면, 심근보호측면에서 정질성 심정지액인 HTK용액은, 혈성 심정지액인 DelNido용액과 비교 시, 혈류역학적 심기능검사상 심박동수의 감소율에서 그리고 생화학적 대사물질검사상 lactate의 증가율에서 우수한 성적을 보였다.

• Journal of Chest Surgery
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• 제29권8호
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• pp.807-815
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• 1996

허혈전처치(ischemic preconditioniiIE)의 허혈심장 보호효과와 그 기전을 규명하기 위한 일환으로 citric oxide(HO)가 허혈전처치의 심보호 효과에 미치는 영향을 검토하였다. 흰쥐 적출심장의 Langendorrr관류표본에서 실험적인 허할(30분)-재관류(30분) 손상을 유도하였고, 허혈전처치는 재관류손상 유도 전에 5분 허혈 - 5분 재관류를 3회 반복하여 시행하였다. 허혈심근 손상의 지표로 심수축기능 세질효소 유출 및 미세형태학적 변화를, 그리고 HO 합성 억제제인 L-HAME 를 투여하여 허혈전처치와 비전처치 허혈-재관류 심장들에서 손상의 정도를 비교하였다. 그 결과 허혈- 재관류 심장에서 심기능의 저하및 세포질 유출이 현저하게 증가하였고 전자현미경상의 미세구조에서도 세포내 소기관 및 myofibril의 파괴가 관찰되 어 심근손상이 심함을 알 수 있었다. 허 혈-재관류에 의한 심 장손상은 허혈전처치를 시행한 허혈-재관류 심장에서는 현격하게 감소돼 심회복률이 77%로 증가하였 고 세포질유출도 현저하게 감소되었으며 미세소견에서도 세포구조가 비교적 잘 보존되었다. 허혈전처 치에 의한 심보호 효과에 NO가 관여하는지를 관찰하기 위하여 NO합성 억제제인 L-NAME를 투여하 여 허혈전처치를 시행하였다. 결과 L-UAME투여로 허혈전처치에 의하여 회복된 심기능 및 LDH유출 감소에 아무런 영향을 주지 않았고 허혈전처치에 의하여 비교적 잘 보존된 미세구조 역시 영향을 받지 않았다. 이상의 결과들로부터 허혈전처치는 세포수준에서 허혈심근의 재관류손상을 방지하며, NO합성의 증가가 횐쥐 적출 심장에서 허혈전처치에 의한 허혈심장 보호효과에 크게 기여하지 않을 것으로 사료되었다.

• 대한한방소아과학회지
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• 제21권1호
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• pp.173-187
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• 2007

Objectives : In order to verify the cardiovascular hemodynamic function of Kammaegdaejo-tang, the experiment was performed in the rats. Methods : Twelve hearts removed from male Sparague-Dawley rats weighing between 250g and 300g were perfused by the Langendorff technique with modified 37 Krebs-Henseleit's buffer solution at a constant perfusion pressure. They were randomly assigned to one of two groups, supplied with either normal saline or Kammaegdaejotang administration. Heart rate, left ventricular pressure, +dp/dt maximum, -dp/dt maximum, and -dp/dt/ +dp/dt ratio were evaluated at baseline after the administration of either normal saline or Kammaegdaejotang. Results : Kammaegdaejotang made the heart rate increasing significantly (p<0.05). Kammaegdaejotang did not effectively work on left ventricular pressure of the isolated heart(p=0.11, no significance). The significant effects of Kammaegdaejotang were observed on +dp/dt max and -dp/dt max(p<0.05). Kammaegdaejotang did not effectively work on -dp/dt/ +dp/dt ratio(p=0.24, no significance).