Influence of Hyperglycemia on Dexmedetomidine-Induced Cardioprotection in the Isolated Perfused Rat Heart

Pharmacological preconditioning (PC) and postconditioning (PoC), for example, by treatment with the α2-adrenoreceptor agonist Dexmedetomidine (Dex), protects hearts from ischemia-reperfusion (I/R) injury in experimental studies, however, translation into the clinical setting has been challenging. Acute hyperglycemia adversely affects the outcome of patients with myocardial infarction. Additionally, it also blocks cardioprotection by multiple pharmacological agents. Therefore, we investigated the possible influence of acute hyperglycemia on Dexmedetomidine-induced pre- and postconditioning. Experiments were performed on the hearts of male Wistar rats, which were randomized into 7 groups, placed in an isolated Langendorff system and perfused with Krebs-Henseleit buffer. All hearts underwent 33 min of global ischemia, followed by 60 min of reperfusion. Control (Con) hearts received Krebs-Henseleit buffer (Con KHB), glucose (Con HG) or mannitol (Con NG) as vehicle only. Hearts exposed to hyperglycemia (HG) received KHB, containing 11 mmol/L glucose (an elevated, but commonly used glucose concentration for Langendorff perfused hearts) resulting in a total concentration of 22 mmol/L glucose throughout the whole experiment. To ensure comparable osmolarity with HG conditions, normoglycemic (NG) hearts received mannitol in addition to KHB. Hearts were treated with 3 nM Dexmedetomidine (Dex) before (DexPC) or after ischemia (DexPoC), under hyperglycemic or normoglycemic conditions. Infarct size was determined by triphenyltetrazoliumchloride staining. Acute hyperglycemia had no impact on infarct size compared to the control group with KHB (Con HG: 56 ± 9% ns vs. Con KHB: 56 ± 7%). DexPC reduced infarct size despite elevated glucose levels (DexPC HG: 35 ± 3%, p < 0.05 vs. Con HG). However, treatment with Dex during reperfusion showed no infarct size reduction under hyperglycemic conditions (DexPoC HG: 57 ± 9%, ns vs. Con HG). In contrast, hearts treated with mannitol demonstrated a significant decrease in infarct size compared to the control group (Con NG: 37 ± 3%, p < 0.05 vs. Con KHB). The combination of Dex and mannitol presents exactly opposite results to hearts treated with hyperglycemia. While DexPC completely abrogates infarct reduction through mannitol treatment (DexPC NG: 55 ± 7%, p < 0.05 vs. Con NG), DexPoC had no impact on mannitol-induced infarct size reduction (DexPoC NG: 38 ± 4%, ns vs. Con NG). Acute hyperglycemia inhibits DexPoC, while it has no impact on DexPC. Treatment with mannitol induces cardioprotection. Application of Dex during reperfusion does not influence mannitol-induced infarct size reduction, however, administering Dex before ischemia interferes with mannitol-induced cardioprotection.

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Abstract 213: TRPV1 Mediates Remote and Direct Cardioprotection

Circulation Research ◽

10.1161/res.113.suppl_1.a213 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Eric R Gross ◽

Travis J Urban ◽

Ana K Hsu ◽

Nir Qvit ◽

Garrett J Gross ◽

...

Keyword(s):

Left Ventricle ◽

Infarct Size ◽

Transient Receptor Potential ◽

Ex Vivo ◽

Isolated Heart ◽

Ischemia Reperfusion ◽

Size Reduction ◽

Cellular Damage ◽

H9c2 Cell ◽

Infarct Size Reduction

Introduction: The transient receptor potential 1 channel (TRPV1) mediates signals from pain, heat, and/or noxious stimuli. TRPV1 sensitization can occur via a protein kinase C (PKC)-dependent mechanism in neurons. Therefore, we tested whether TRPV1 is a mediator of cardioprotection in models of ischemia-reperfusion and whether the molecular mechanism of cardioprotection occurs via PKC-induced TRPV1 channel sensitization. Methods: Male Sprague Dawley rats and H9C2 left ventricle-derived cells were used for whole animal and cellular ischemia-reperfusion studies to test this hypothesis. Statistical analysis regarding infarct size, calculated as percentage of area at risk per left ventricle, was performed by a one way ANOVA (*P<0.01). Results: Remote preconditioning-induced infarct size reduction via an abdominal surgical incision was blocked by prior administration of a selective TRPV1 peptide inhibitor, V1-B (3.0mg/kg), given over the incision site (Incision: 44±2*% V1-B+Incision: 65±2% versus Control: 64±1% n=6/group). Capsaicin (0.3mg/kg) given intravenously through the internal jugular vein reduced infarct size in vivo , which was blocked by prior capsazepine (TRPV1 inhibitor, 3.0mg/kg) administration (Capsaicin: 43±2* Capsaicin+ capsazepine: 64±4 versus Control: 62±3, n=7/group). Further in an ex vivo isolated heart model, infarct size reduction afforded by the selective epsilon PKC activator (pseudo epsilon RACK, 1uM) was partially blocked with prior treatment of V1-B (1uM), the TRPV1 peptide blocker (pseudo epsilon RACK: 20±2*%, pseudo epsilon RACK+V1-B: 42±4% versus control: 47±4%, n=7/group). TRPV1 expression was found in both whole heart homogenate and in the H9C2 cell line. Using a model of ischemia-reoxygenation in H9C2 cells, capsaicin treatment before and during ischemia-reoxygenation reduced cellular damage as assessed by MTT and LDH assays. Greater damage occurred with TRPV1 inhibition by capsazepine compared to control. Conclusions: Our studies suggest TRPV1 contributes an essential role for both remote and direct cardioprotection. Further studies are ongoing to determine the post-translational sites on TRPV1 and how a TRPV1-epsilon PKC protein-protein interaction induces cardioprotection.

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Cardiac MRI detection of infarct size reduction with hypothermia in porcine ischemia reperfusion injury model

Journal of Cardiovascular Magnetic Resonance ◽

10.1186/1532-429x-17-s1-p115 ◽

2015 ◽

Vol 17 (Suppl 1) ◽

pp. P115

Author(s):

Rajesh Dash ◽

Atsushi Tachibana ◽

Yoshiaki Mitsutake ◽

Fady Dawoud ◽

Fumiaki Ikeno ◽

...

Keyword(s):

Infarct Size ◽

Reperfusion Injury ◽

Cardiac Mri ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Size Reduction ◽

Injury Model ◽

Infarct Size Reduction

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Impact of Anesthetics on Cardioprotection Induced by Pharmacological Preconditioning

Journal of Clinical Medicine ◽

10.3390/jcm8030396 ◽

2019 ◽

Vol 8 (3) ◽

pp. 396 ◽

Cited By ~ 6

Author(s):

Sebastian Bunte ◽

Tobias Lill ◽

Maximilian Falk ◽

Martin Stroethoff ◽

Annika Raupach ◽

...

Keyword(s):

Infarct Size ◽

Ischemic Preconditioning ◽

Wistar Rats ◽

Constant Pressure ◽

Size Reduction ◽

Control Groups ◽

Infarct Size Reduction ◽

Male Wistar Rats ◽

Pharmacological Preconditioning ◽

Krebs Henseleit Buffer

Anesthetics, especially propofol, are discussed to influence ischemic preconditioning. We investigated whether cardioprotection by milrinone or levosimendan is influenced by the clinically used anesthetics propofol, sevoflurane or dexmedetomidine. Hearts of male Wistar rats were randomised, placed on a Langendorff system and perfused with Krebs–Henseleit buffer (KHB) at a constant pressure of 80 mmHg. All hearts underwent 33 min of global ischemia and 60 min of reperfusion. Three different anesthetic regimens were conducted throughout the experiments: propofol (11 μM), sevoflurane (2.5 Vol%) and dexmedetomidine (1.5 nM). Under each anesthetic regimen, pharmacological preconditioning was induced by administration of milrinone (1 μM) or levosimendan (0.3 μM) 10 min before ischemia. Infarct size was determined by TTC staining. Infarct sizes in control groups were comparable (KHB-Con: 53 ± 9%, Prop-Con: 56 ± 9%, Sevo-Con: 56 ± 8%, Dex-Con: 53 ± 9%; ns). Propofol completely abolished preconditioning by milrinone and levosimendan (Prop-Mil: 52 ± 8%, Prop-Lev: 52 ± 8%; ns versus Prop-Con), while sevoflurane did not (Sevo-Mil: 31 ± 9%, Sevo-Lev: 33 ± 7%; p < 0.05 versus Sevo-Con). Under dexmedetomidine, results were inconsistent; levosimendan induced infarct size reduction (Dex-Lev: 36 ± 6%; p < 0.05 versus Dex-Con) but not milrinone (Dex-Mil: 51 ± 8%; ns versus Dex-Con). The choice of the anesthetic regimen has an impact on infarct size reduction by pharmacological preconditioning.

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The independent effects of oxygen radical scavengers on canine infarct size. Reduction by superoxide dismutase but not catalase.

Circulation Research ◽

10.1161/01.res.56.6.895 ◽

1985 ◽

Vol 56 (6) ◽

pp. 895-898 ◽

Cited By ~ 167

Author(s):

S W Werns ◽

M J Shea ◽

E M Driscoll ◽

C Cohen ◽

G D Abrams ◽

...

Keyword(s):

Superoxide Dismutase ◽

Infarct Size ◽

Oxygen Radical ◽

Size Reduction ◽

Radical Scavengers ◽

Infarct Size Reduction ◽

Independent Effects

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Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01048.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. H859-H866 ◽

Cited By ~ 76

Author(s):

Istvan Lekli ◽

Gergo Szabo ◽

Bela Juhasz ◽

Samarjit Das ◽

Manika Das ◽

...

Keyword(s):

Body Weight ◽

Ventricular Fibrillation ◽

Infarct Size ◽

Ischemia Reperfusion ◽

Serum Glucose ◽

Control Group ◽

Glut 4 ◽

Reduced Body ◽

Glucose Intake ◽

Obese Rats

The resveratrol-induced cardiac protection was studied in Zucker obese rats. Rats were divided into five groups: group 1, lean control; group 2, obese control (OC); group 3, obese rats treated orally with 5 mg·kg−1·day−1 of resveratrol (OR) for 2 wk; group 4, obese rats received 10% glucose solution ad libitum for 3 wk (OG); and group 5, obese rats received 10% glucose for 3 wk and resveratrol (OGR) during the 2nd and 3rd wk. Body weight, serum glucose, and insulin were measured, and then hearts were isolated and subjected to 30 min of ischemia followed by 120 min of reperfusion. Heart rate, coronary flow, aortic flow, developed pressure, the incidence of reperfusion-induced ventricular fibrillation, and infarct size were measured. Resveratrol reduced body weight and serum glucose in the OR compared with the OC values (414 ± 10 g and 7.08 ± 0.41 mmol/l, respectively, to 378 ± 12 g and 6.11 ± 0.44 mmol/l), but insulin levels were unchanged. The same results were obtained for the OG vs. OGR group. Resveratrol improved postischemic cardiac function in the presence or absence of glucose intake compared with the resveratrol-free group. The incidence of ventricular fibrillation and infarct size was reduced by 83 and 20% in the OR group, and 67 and 16% in the OGR group, compared with the OC and OG groups, respectively. Resveratrol increased GLUT-4 expression and reduced endothelin expression and cardiac apoptosis in ischemic-reperfused hearts in the presence or absence of glucose intake. Thus the protective effect of resveratrol could be related to its direct effects on the heart.

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Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.5.r1468 ◽

1998 ◽

Vol 275 (5) ◽

pp. R1468-R1477 ◽

Cited By ~ 63

Author(s):

Scott K. Powers ◽

Haydar A. Demirel ◽

Heather K. Vincent ◽

Jeff S. Coombes ◽

Hisashi Naito ◽

...

Keyword(s):

Lipid Peroxidation ◽

Exercise Training ◽

Endurance Exercise ◽

Ischemia Reperfusion ◽

Experimental Studies ◽

Control Group ◽

Sprague Dawley ◽

Endurance Exercise Training ◽

Nonprotein Thiols

Experimental studies examining the effects of regular exercise on cardiac responses to ischemia and reperfusion (I/R) are limited. Therefore, these experiments examined the effects of endurance exercise training on myocardial biochemical and physiological responses during in vivo I/R. Female Sprague-Dawley rats (4 mo old) were randomly assigned to either a sedentary control group or to an exercise training group. After a 10-wk endurance exercise training program, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 20 min, followed by a 10-min period of reperfusion. Compared with untrained, exercise-trained animals maintained higher ( P < 0.05) peak systolic blood pressure throughout I/R. Training resulted in a significant ( P < 0.05) increase in ventricular nonprotein thiols, heat shock protein (HSP) 72, and the activities of superoxide dismutase (SOD), phosphofructokinase (PFK), and lactate dehydrogenase. Furthermore, compared with untrained controls, left ventricles from trained animals exhibited lower levels ( P < 0.05) of lipid peroxidation after I/R. These data demonstrate that endurance exercise training improves myocardial contractile performance and reduces lipid peroxidation during I/R in the rat in vivo. It appears likely that the improvement in the myocardial responses to I/R was related to training-induced increases in nonprotein thiols, HSP72, and the activities of SOD and PFK in the myocardium.

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