• The Korean Journal of Physiology and Pharmacology
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• v.8 no.2
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• pp.95-100
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• 2004

Ischemic preconditioning (IPC) has been accepted as a heart protection phenomenon against ischemia and reperfusion (I/R) injury. The activation of ATP-sensitive potassium $(K_{ATP})$ channels and the release of myocardial nitric oxide (NO) induced by IPC were demonstrated as the triggers or mediators of IPC. A common action mechanism of NO is a direct or indirect increase in tissue cGMP content. Furthermore, cGMP has also been shown to contribute cardiac protective effect to reduce heart I/R-induced infarction. The present investigation tested the hypothesis that $K_{ATP}$ channels attenuate DNA strand breaks and oxidative damage in an in vitro model of I/R utilizing rat ventricular myocytes. We estimated DNA strand breaks and oxidative damage by mean of single cell gel electrophoresis with endonuclease III cutting sites (comet assay). In the I/R model, the level of DNA damage increased massively. Preconditioning with a single 5-min anoxia, diazoxide $(100\;{\mu}M)$, SNAP $(300\;{\mu}M)$ and 8-(4-Chlorophenylthio)-guanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP) $(100\;{\mu}M)$ followed by 15 min reoxygenation reduced DNA damage level against subsequent 30 min anoxia and 60 min reoxygenation. These protective effects were blocked by the concomitant presence of glibenclamide $(50\;{\mu}M)$, 5-hydroxydecanoate (5-HD) $(100\;{\mu}M)$ and 8-(4-Chlorophenylthio)-guanosine-3',5'-cyclic monophosphate, Rp-isomer (Rp-8-pCPT-cGMP) $(100\;{\mu}M)$. These results suggest that NO-cGMP-protein kinase G (PKG) pathway contributes to cardioprotective effect of $K_{ATP}$ channels in rat ventricular myocytes.

• Journal of Chest Surgery
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• v.13 no.4
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• pp.321-337
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• 1980

The increasing use of cardioplegic solution for the reduction of ischemic tissue injury requires that all cardiplegic solution be carefully assessed for any protective or damaging properties. This study describes functional, enzymatic and structural assessment of the efficiency of three cardioplegic solutions (Young & GIK, Bretschneider, and $K^{+}$ Albumin solution) in a Modified Isolated Rat Heart Model of cardiopulmonary bypass and ischemic arrest. Isolated rat heart were subjected to a 2-minute period of coronary infusion with a cold cardioplegic or a noncardioplegic solution immediately before and also at the midpoint of a 60-minute period of hypothermic ($10{\pm}1$. C) ischemic cardiac arrest. The results of this study were as follow: 1. Spontaneous heart beat after ischemic arrest occured 16 seconds later after Langendorff reperfusion in the Young & GIK group (n=6), and 40 second later in the Bretschneider group (n=6) and 6 minute later in the $K^{+}$ Albumin group (n=6), and 16 minute later in the control group (non-cardioplegia). A good recovery state of spontaneous heart beat was shown in the Young & GIK and Bretschneider groups. 2. The percentage of recorveries of heart function at 30 minute after postischemic working heart perfusion were : heart rate $91.6{\pm}3.1$% (P<0.01)m oeaj airtuc oressyre $83{\pm}3$% (P<0.01), coronary flow $70{\pm}8$% (P<0.05) and aortic flow flow rate $39{\pm}9.3$% (P<0.05) in the Young & GIK group. This percentage of recoveries of the Young & GIK group was significantly greater than the control group. In the Bretschneider group, the percentage of recoveries were : heart rate $87.8{\pm}7.5$%(P<0.05), peak aortic pressure $71{\pm}2.3$% (P<0.05) and aortic flow rate $33.2{\pm}6.6$%(P<0.05). hte percentage of recoveries were significantly greater than in the control group. In the $K^{+}$ Albumin group, recoveries of heart function were poor. 3. Total CPK leakage was $131.2{\pm}12.75$IU/30 min/gm. dry weight in the control group, $50.65{\pm}12.75$IU in the Young & GIK gruop, $69.40{\pm}32.21$Iu in Bretschneider group, and $103.65{\pm}15.47$IU in the $K^{+}$ Albumin group during the 30 minute postischemic Langendorff reperfusion. Total CPK leakage was significantly less (P<0.001) in the Young & GIK group, than in the control group. 4. Direct correlatin between percentage recovery of aortic flow rate and total amount of CPK leakage from Myocardium was noticed.(Correlation Coefficient r = 0.76, P<0.001). 5. Mild perivascular edema was the only finding of light microscopic study of myocardium after 60 minute ischemic arrest with cold cardioplegic solutions and hypothermla.

• Journal of Chest Surgery
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• v.30 no.2
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• pp.119-124
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• 1997

Using isolated rat heart preparations, we observed the protective effe ts of verapamil cardioplegia on ischemic myocardial injury. Isolated rat hearts were subjected to global ischemia at $25^{\circ}C$ Twenty four isolated Sprague Dawley rat hearts underwent 30 minutes of the retrograde nonworking perfusion with Krebs-Henseleit buffer solution followed by $25^{\circ}C$ cardioplegic solution (St. Thomas'Hospital Cardioplegic Solution) for 60 minutes. Before ischemic arrest, rat hearts were treated with cold cardioplegic solution in control group (n=12) and cold cardioplegic solution with verapamil (1 mg/L) in experimental group (n=12). After 60 minutes of ischemia, hemodynamic and biochemical parameters such as heart rate, left ventricular pressure (LVP), + dp/dt max, coronary flow and creatine phosphokinase (CPK) were measured before giving cardioplegia and 30 minutes after reperfusion. Verapamil group exhibited greater recovery of heart rate, LVP, +dpldt max, coronary flow and CPK than control group (p < 0.05).

• Journal of Chest Surgery
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• v.36 no.11
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• pp.828-833
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• 2003

Background: It has been reported that the recently developed intermittent antegrade warm blood cardioplegia (IAWBC) has better myocardial protective effects during coronary artery bypass surgery than cold blood cardioplegia or continuos retrograde cold blood cardioplegia. The aim of this study is to evaluate the safety and usefulness of IAWBC by comparing it retrospectively with intermittent retrograde cold blood cardioplegia (lRCBC). Material and Method: From April 2001 to Feb. 2003, fifty seven patients who underwent isolated coronary surgery were divided into two groups (IAWBC vs. IRCBC). The two group had similar demographic and angiographic characteristics. There were no statistical differences in age, sex, Canadian Cardiovascular Society Functional Classification for angina, ejection fraction, and number of grafts. Result: Aortic cross clamping time and total pump time in IAWBC (99$\pm$23 and vs. 126$\pm$32 min) were shorter than those of IRCBC (118$\pm$32 min. and 185$\pm$48 min.)(p<0.05). The reperfusion time (13$\pm$7 min) in IAWBC was shorter than that of IRCBC (62$\pm$109 min.)(p<0.05). CKMB at 12 hours and 24 hours (16$\pm$15 and 9$\pm$13) in IAWBC was lower than that of IRCBC (33$\pm$47 and 17$\pm$26)(p<0.05). The awakening time in IAWBC (2$\pm$1 hour) was shorter than that of IRCBC (4$\pm$3)(p<0.05). The number of spontaneous heart beat recovery in IAWBC (85%) was more than that of IRCBC (35%)(p<0.05). The cardiac index after discontinuing cardio-pulmonary bypass was significantly elevated in the IAWBC group. The prevalence of perioperative myocardial infarction in IAWBC (4%) was lower than that of IRCBC group (20%)(p<0.05). Conclusion: Intermittent antegrade warm blood cardioplegia is a safe, reliable, and effective technique for myocardial protection. It can also provide simpler and economic way than the retrograde cold cardioplegia by shortening of cardiopulmonary bypass time and avoiding retrograde cannulation for coronary sinus.

• Journal of Chest Surgery
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• v.34 no.7
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• pp.524-533
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• 2001

Background: Hyperoxemic cardiopulmonary bypass (CPB) has been recognized as a safe technique and is widely used in cardiac surgery. However, hyperoxemic CPB may produce higher toxic oxygen species and cause more severe oxidative stress and ischemia/reperfusion injury than normoxemic CPB. This study was undertaken to compare inflammatory responses and myocardial injury between normoxemic and hyperoxemic CPB and to examine the beneficial effect of normoxemic CPB. Material and method: Thirty adult patients scheduled for elective cardiac surgery were randomly divided into normoxic group (n=15), who received normoxemic CPB (about Pa $O_{2}$ 120 mmHg), and hyperoxic group (n=15), who received hyperoxemic CPB (about Pa $O_{2}$ 400 mmHg). Myeloperoxidase (MPO), malondialdehyde (MDA), adenosine monophosphate (AMP), and troponin-T (TnT) concentrations in coronary sinus blood were determined at pre- and post-CPB. Total leukocyte and neutrophil counts in arterial blood were measured at the before, during, and after CPB. Lactate concentration in mixed venous blood was analyzed during CPB, and cardiac index (Cl) and pulmonary vascular

• Journal of Chest Surgery
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• v.42 no.5
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• pp.576-587
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• 2009

Background: The up-regulation of the nitric oxide (NO)-cGMP pathway might be involved in the change of vascular reactivity in rats 3 days after they suffer acute myocardial infarction. However, the underlying mechanism for this has not been clarified. Material and Method: Acute myocardial infarction (AMI) was induced by occluding the left anterior descending coronary artery (LAD) for 30 min (Group AMI), whereas the sham-operated control rats were treated similarly without LAD occlusion (Group SHAM), The concentration-response relationships for phenylephrine (PE), KCl, acetylcholine (Ach) and sodium nitroprusside (SNP) were determined in the endothelium intact E(+) and endothelium denuded E(-) thoracic aortic rings from the rats 3 days after AMI or a SHAM operation. The concentration-response relationships of PE in the E(+) rings from the AMI rats were compared with those relationships in the rings pretreated with nitric oxide synthase (NOS) inhibitor $N{\omega}$-nitro-L-arginine methyl ester (L-NAME) or the cyclooxygenase inhibitor indomethacin. The plasma nitrite/nitrate concentrations were checked via a Griess reaction. The cyclic GMP content in the thoracic aortic rings was measured by radioimmunoassay and the endothelial nitric oxide synthase (eNOS) mRNA expression was assessed by real time PCR. Result: The mean infarct size (%) in the rats with AMI was $21.3{\pm}0.62%$. The heart rate and the systolic and diastolic blood pressure were not significantly changed in the AMI rats. The sensitivity of the contractile response to PE and KCl was significantly decreased in both the E(+) and E(-) aortic rings of the AMI group (p<0.05). L-NAME completely reversed these contractile responses whereas indomethacin did not (p<0.05). Moreover, the sensitivity of the relaxation response to Ach was also significantly decreased in the AMI group (p<0.05). The plasma nitrite and nitrate content (p<0.05), the basal cGMP content (p<0.05) and the eNOS mRNA expression (p=0.056) in the AMI rats were increased as compared with the SHAM group. Conclusion: Our findings indicate that the increased eNOS activity and the up-regulation of the NO-cGMP pathway can be attributed to the decreased contractile or relaxation response in the rat thoracic aorta 3 days after AMI.

• Journal of Chest Surgery
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• v.31 no.5
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• pp.502-508
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• 1998

Proinflammatory cytokines such as tumor necrosis factor-$\alpha$(TNF-$\alpha$) have been implicated in myocardial and organ dysfunction associated with postperfusion syndrome. We tested the hypothesis that cytokine productions are depressed by preoperative cortiosteroid injection for cardiopulmonary bypass(CPB) and the postoperative courses will be better than without steriod pretreated cases. Cardiac surgery was performed in randomized blind fashion for 20 patients from June 1996 to September 1996. In the steroid group(n=10), corticosteroid(dexamethasone 1 mg/kg) was injected 1 hour before anesthetic induction, but in the control group(n=10), nothing was injected. Each of groups were sampled 11 times as scheduled for TNF-$\alpha$ bioassays. We have checked EKG, cardiac enzymes(CPK, LDH with isoenzyme), WBC count preoperative day, one day and three days after operation. Viatal signs were continuously monitored for three postoperaive days. In the postoperative period three patients in the control group had elevated body temperature and four patients had hypotension that required considerable intravenous fluid administration. But steroid injected patients showed normal body temperture and acceptable blood pressures without supportive treatment. CPK enzymes rose in control group higher than steroid group at postoperative 1st and 3rd day(CPK; 1122$\pm$465 vs 567$\pm$271, 864$\pm$42 vs 325$\pm$87), and CPK-MB enzymes rose in control group higher than steroid group at postoperative 1st day(106.4$\pm$115.1 vs 29.5$\pm$22.4)(P=0.02). Arterial tumor necrosis factor-$\alpha$ rose during cardiopulmonary bypass, peaking at 5 minutes before the end of aortic cross clamping(ACC-5min) in steroid group(11.9$\pm$4.7 pg/ml), and 5 minutes before the end of cardiopulmonary bypass(CPB-5min) in control group(22.3$\pm$6.8 pg/ml). The steroid pretreated patients had a shorter period of time in respirator suport time, ICU stay day, hospital admission day. We conclude that corticosteroid suppress cytokine production during and after cardiopulmonary bypass, and may improve the postoperative course through inhibition of reperfusion injury such as myocardial stunning and hemodynamic instability.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.3
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• pp.293-300
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• 2017

Prostaglandin $D_2$ ($PGD_2$) may act against myocardial ischemia-reperfusion (I/R) injury and play an anti-inflammatory role in the heart. Although the effect of $PGD_2$ in regulation of ANP secretion of the atrium was reported, the mechanisms involved are not clearly identified. The aim of the present study was to investigate whether $PGD_2$ can regulate ANP secretion in the isolated perfused beating rat atrium, and its underlying mechanisms. $PGD_2$ (0.1 to $10{\mu}M$) significantly increased atrial ANP secretion concomitantly with positive inotropy in a dose-dependent manner. Effects of $PGD_2$ on atrial ANP secretion and mechanical dynamics were abolished by AH-6809 ($1.0{\mu}M$) and AL-8810 ($1.0{\mu}M$), $PGD_2$ and prostaglandin $F2{\alpha}$ ($PGF2{\alpha}$) receptor antagonists, respectively. Moreover, $PGD_2$ clearly upregulated atrial peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) and the $PGD_2$ metabolite 15-deoxy-${\Delta}12$, 14-$PGJ_2$ (15d-$PGJ_2$, $0.1{\mu}M$) dramatically increased atrial ANP secretion. Increased ANP secretions induced by $PGD_2$ and 15d-$PGJ_2$ were completely blocked by the $PPAR{\gamma}$ antagonist GW9662 ($0.1{\mu}M$). PD98059 ($10.0{\mu}M$) and LY294002 ($1.0{\mu}M$), antagonists of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling, respectively, significantly attenuated the increase of atrial ANP secretion by $PGD_2$. These results indicated that $PGD_2$ stimulated atrial ANP secretion and promoted positive inotropy by activating $PPAR{\gamma}$ in beating rat atria. MAPK/ERK and PI3K/Akt signaling pathways were each partially involved in regulating $PGD_2$-induced atrial ANP secretion.

• Journal of Chest Surgery
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• v.35 no.3
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• pp.199-208
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• 2002

Background: The washing of packed red blood cells could remove pro-inflammatory mediators, cell debris, and micro-particles contained in packed red blood cells, and the preci-rculation-ultrafiltration (recirculation and ultrafiltration of circuit itself before cardiopulmonary bypass) could attenuate the initial inflammatory reaction and remove the initial proinflam-matory mediators. This study was performed to evaluate whether the washing of packed red blood cells and precirculation-ultrafiltration can reduce the production of cytokines that have an important role in myocardial reperfusion injury. This study investigated the effects of washing the packed red blood cells and precirculation-ultrafiltration on the production of cytokines during and after cardiopulmonary bypass and open heart surgery. Material and Method: Forty eight infants with VSD undergoing open heart surgery under cardiopulmonary bypass were randomized into control group (group C, n=12), washing group (group W, n= 12), precirculation-ultrafiltration group (group F, n: 12), and combined group(washing and precirculation-ultrafiltration, group WF, n=12). Blood samples were obtained before, during, and after the bypass to assess plasma level of tumor necrosis factor-$\alpha$(TNF-$\alpha$), interleukin-6(IL-6), and interleukin-8 (IL-8). Results: Expressions of TNF-$\alpha$ were significantly reduced in combined group (group WF) compared with group C, group W, and group F (p<0.05). Expression of IL-6 were significantly reduced in group W, group F, and group WF compared with group C (p<0.05), but similar among group W, group F, and group WF (p=0.053). Expression of IL-8 were reduced in group W and group WF compared with group C (p<0.05), but similar among group W, group F, and group WF (p=0.067). Conclusion: In conclusion, the washing of packed red blood cells and precirculation-ultrafiltration blunted the increase of TNF-$\alpha$ , IL-6, and IL-8 during and after open heart surgery with cardiopulmonary bypass. However, the clinical benefits of these treatments remains unproven.