Suspended animation is defined as the therapeutic induction of a state of tolerance to temporary complete systemic ischemia, i.w., protection-preservation of the whole organism during prolonged circulatory arrest ( > or = 1 hr), followed... more
Suspended animation is defined as the therapeutic induction of a state of tolerance to temporary complete systemic ischemia, i.w., protection-preservation of the whole organism during prolonged circulatory arrest ( > or = 1 hr), followed by resuscitation to survival without brain damage. The objectives of suspended animation include: a) helping to save victims of temporarily uncontrollable (internal) traumatic (e.g., combat casualties) or nontraumatic (e.g., ruptured aortic aneurysm) exsanguination, without severe brain trauma, by enabling evacuation and resuscitative surgery during circulatory arrest, followed by delayed resuscitation; b) helping to save some nontraumatic cases of sudden death, seemingly unresuscitable before definite repair; and c) enabling selected (elective) surgical procedures to be performed which are only feasible during a state of no blood flow. In the discussion session, investigators with suspended animation-relevant research interests brainstorm on present knowledge, future research potentials, and the advisability of a major research effort concerning this subject. The following topics are addressed: the epidemiologic facts of sudden death in combat casualties, which require a totally new resuscitative approach; the limits and potentials of reanimation research; complete reversibility of circulatory arrest of 1 hr in dogs under profound hypothermia ( < 10 degrees C), induced and reversed by portable cardiopulmonary bypass; the need for a still elusive pharmacologic or chemical induction of suspended animation in the field; asanguinous profound hypothermic low-flow with cardiopulmonary bypass; electric anesthesia; opiate therapy; lessons learned by hypoxia tolerant vertebrate animals, hibernators, and freeze-tolerant animals (cryobiology); myocardial preservation during open-heart surgery; organ preservation for transplantation; and reperfusion-reoxygenation injury in vital organs, including the roles of nitric oxide and free radicals; and how cells (particularly cerebral neurons) die after transient prolonged ischemia and reperfusion. The majority of authors believe that seeking a breakthrough in suspended animation is not utopian, that ongoing communication between relevant research groups is indicated, and that a coordinated multicenter research effort, basic and applied, on suspended animation is justified.
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AIMS: This study aims to investigate the role of peripheral δ2 opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, KATP channels and the autonomic nervous system in δ2... more
AIMS: This study aims to investigate the role of peripheral δ2 opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, KATP channels and the autonomic nervous system in δ2 cardioprotection. MAIN METHODS: ...
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Recent studies have confirmed that ischemic preconditioning prevents appearance of reperfusion endothelial dysfunction. However, the issue of preconditioning impact on no-reflow phenomenon remains unresolved. The receptor mechanisms... more
Recent studies have confirmed that ischemic preconditioning prevents appearance of reperfusion endothelial dysfunction. However, the issue of preconditioning impact on no-reflow phenomenon remains unresolved. The receptor mechanisms involved in the cardioprotective and vasoprotective effects of preconditioning are different. The ability of preconditioning in preventing reperfusion endothelial dysfunction is dependent upon bradykinin B2-receptor activation and not dependent upon adenosine receptor stimulation. The vasoprotective effect of preconditioning is mediated via mechanisms relying in part on activation of protein kinase C, NO-synthase, cyclooxygenase, mitochondrial K(ATP)-channel opening and an enhancement of antioxidative protection of the heart. The delayed preconditioning also exerts endothelium-protective effect. Peroxynitrite, NO* and O2* are the triggers of this effect but a possible end-effector involves endothelial NO-synthase.
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Preliminary stimulation of cardiac delta1-opioid receptors by DPDPE addition at a concentration of 0.1 mg/liter to the perfusion solution decreased the incidence of reperfusion arrhythmias and the reperfusive destruction of cardiac cells.... more
Preliminary stimulation of cardiac delta1-opioid receptors by DPDPE addition at a concentration of 0.1 mg/liter to the perfusion solution decreased the incidence of reperfusion arrhythmias and the reperfusive destruction of cardiac cells. At the same time, the activation of cardiac delta1-opioid receptors resulted in a decrease in myocardial contractility both in the pre-ischemic period and upon restoration of the coronary flow. Pretreatment with naltriondole (a delta-receptor antagonist) or with cyclopiazonic acid (a specific inhibitor of Ca2+ uptake in sarcoplasmic reticulum) completely abolished the antiarrhythmic, cardioprotective, and inotropic effects of DPDPE. It is suggested that the antiarrhythmic, cardioprotective, and inotropic effects of DPDPE is related to the cardiac delta1-opioid receptor activation and Ca2+ transport alteration on the level of sarcoplasmic reticulum.
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Background: Consistent clinical results have not been achieved when lung preservation times exceed 6 hours. The aim of this study was to use an alternative normothermic autoperfusion technique for lung preservation and transplantation.... more
Background: Consistent clinical results have not been achieved when lung preservation times exceed 6 hours. The aim of this study was to use an alternative normothermic autoperfusion technique for lung preservation and transplantation. Methods: In six paired dogs, donor lungs were removed, along with the heart, liver, pancreas, duodenum, and both kidneys, and were preserved for 24 to 33 hours in a normothermic autoperfused multiple organ block. Orthotopic left lung transplantation was performed at the end of the preservation period. Results: Lung function was good during the preservation period. With a gas mixture of 50% O2 + 3% CO2 + 47% N2 delivered to the multiorgan block, arterial oxygen tension ranged from 331 +/- 19 to 383 +/- 8 mm Hg; carbon dioxide tension ranged from 18 +/- 5 to 32 +/- 5 mm Hg; and pH ranged from 7.36 +/- 0.02 to 7.45 +/- 0.08. After transplantation, the dogs were kept anesthetized and ventilated for 24 hours with the same gas mixture. The opposite pulmonary artery was occluded 0 to 6 hours after transplantation. Arterial blood pressures were stable after surgery. Arterial oxygen tension was maintained between 205 +/- 39 and 320 +/- 57 mm Hg, and arterial carbon dioxide tension was maintained between 23 +/- 2 and 34 +/- 2 mm Hg. Lung tissue wet/dry weight ratio was 4.94 +/- 0.17 after preservation; this ratio did not differ from that found in normal controls (4.91 +/- 0.10). Conclusions: This study shows that the lungs were well preserved for more than 24 hours of preservation when the normothermic multiorgan block preparation was used. The transplanted left lung was able to support the anesthetized dog after the opposite pulmonary artery was occluded.
Research Interests: Carbon Dioxide, Medicine, Transplantation, Dogs, Pubmed, and 12 moreAnimals, Temperature, Lung, Organ Preservation, Oxygen, Time Factors, Heart and Lung Transplantation, Pulmonary Gas Exchange, Postoperative Complications, Lung Transplantation, Respiratory function tests, and Cardiovascular medicine and haematology
Background: Hypothermic cardioplegia provides myocellular protection, yet postischemic dysfunction remains a significant problem. Interestingly, the subcellular changes in hibernation parallel the altered biology of induced cardiac... more
Background: Hypothermic cardioplegia provides myocellular protection, yet postischemic dysfunction remains a significant problem. Interestingly, the subcellular changes in hibernation parallel the altered biology of induced cardiac ischemia but are well tolerated by hibernated mammalian myocardium. An uncharacterized factor derived from hibernating animals, hibernation induction trigger (HIT), has been shown to induce hibernation in active animals and afford myocardial protection after ischemia-reperfusion injury. Therefore, it was of interest to further characterize the cardioprotective effects of HIT in the setting of ischemia-reperfusion injury. Methods and results: To determine whether HIT could improve myocardial recovery after global ischemia, isolated rabbit hearts received either standard cardioplegia or HIT in the cardioplegia or underwent preperfusion with HIT before cardioplegia. Alternatively, to determine whether HIT requires metabolic alteration, additional rabbits had in vivo pretreatment with HIT from 15 minutes to 5 days before ischemia. All hearts underwent 2 hours of global ischemia at 34 degrees C. Recovery of postischemic isovolumic developed pressure, coronary flows, and MVO2 were compared. Compared with vehicle pretreatment, HIT pretreatment (1 hour) significantly enhanced indexes of functional recovery, including developed pressure (38 +/- 3 versus 69 +/- 7 mm Hg) and coronary flow (46 +/- 2 versus 82 +/- 11 mL/min). In addition, ultrastructural morphology was preserved but only with in vivo pretreatment. Liver protein content was not increased in rabbits treated from 12 hours to 5 days with HIT versus controls, belying a protein neosynthesis mechanism. However, the temporal sequences suggested conversion of an inactive HIT profactor to an active form. Conclusions: Administration of serum derived from hibernating black bears to rabbits affords protection against ischemia-reperfusion injury compared with vehicle (saline)-treated animals in a rabbit isolated heart preparation. It is apparent that HIT deserves further identification and mechanistic study in the setting of ischemia-reperfusion injury.
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Age and diabetes are risk factors for arterial hypertension. However, the relationship between age, connective tissue growth factors, vascular aging and arterial hypertension while on a the high-carbohydrate high-fat diet (HCHFD) remains... more
Age and diabetes are risk factors for arterial hypertension. However, the relationship between age, connective tissue growth factors, vascular aging and arterial hypertension while on a the high-carbohydrate high-fat diet (HCHFD) remains poorly understood. To estimate the relationship between humoral factors, the morphological changes of aorta and impaired blood pressure regulation under the influence of age and a HCHFD. A study was carried out in male Wistar rats, which were divided into the following groups: 1st (n = 15) - naive young rats; 2nd (n = 15) - young rats, exposed to HCHFD; 3rd (n = 14) - naive old rats; 4th (n = 12) - old rats exposed to HCHFD. The age of old rats was 540 days, and young rats 150 days at the end of the diet. HCHFD contained proteins 16%, fats 21%, carbohydrates 46%, including 17% fructose, 0.125% cholesterol, 90 days. Blood pressure and body weight were measured weekly, carbohydrate metabolism, histological signs of changes in the aorta, serum transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), fibronectin, and endothelin-1 levels were determined one week after the onset of diet. The severity of arterial hypertension and its histological signs in the aortic wall was found to be most pronounced in elderly rats kept on a HCHFD. In young rats kept on a HCHFD, arterial hypertension was transient. An increase in systolic blood pressure has a positive correlation with the degree of obesity, serum fibronectin, and endothelin-1 content, and impaired carbohydrate metabolism. The rise in diastolic blood pressure has a positive correlation with the serum CTGF, endothelin-1, fibronectin levels and aortic wall thickness, and impaired carbohydrate metabolism. A rise in the serum concentration of fibronectin was also associated with increased endothelin-1, TGFβ and CTGF serum levels. This study indicated that an increase in blood pressure in old rats with a high-carbohydrate high-fat diet is due to a disturbance of a structure of the vascular wall, the release of fibronectin, which can occur under the influence of carbohydrate metabolism disorders, endothelin-1, TGFβ and CTGF.
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... effects of low-fat and low-fat plus high-fiber diets on serum lipid concentrations13 James WAnderson, Thomas F Garrity, Constance L Wood, Sarah E Whitis, Belinda M Smith, and Peter R Oeltgen ABSTRACI&#x27; Previous studies... more
... effects of low-fat and low-fat plus high-fiber diets on serum lipid concentrations13 James WAnderson, Thomas F Garrity, Constance L Wood, Sarah E Whitis, Belinda M Smith, and Peter R Oeltgen ABSTRACI&#x27; Previous studies examining the hypocholes-...
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... PhD; Ernster, Lars PhD; Hattler, Brack G. Jr MD; Hochachka, Peter PhD; Klain, Miroslav MD PhD; Kochanek, Patrick M. MD FCCM; Kofke, W. Andrew MD FCCM; Lancaster, Jack R. PhD ... Designed in 1995 by P. Safar, MD, and P. Kochanek, MD,... more
... PhD; Ernster, Lars PhD; Hattler, Brack G. Jr MD; Hochachka, Peter PhD; Klain, Miroslav MD PhD; Kochanek, Patrick M. MD FCCM; Kofke, W. Andrew MD FCCM; Lancaster, Jack R. PhD ... Designed in 1995 by P. Safar, MD, and P. Kochanek, MD, with input from N. Bircher, MD, and ...
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The metabolic effects of high-carbohydrate (70%), high-fiber (70 g) (HCHF) and low-carbohydrate (39%), low-fiber (10 g) (LCLF) diets were examined for 10 subjects with insulin-dependent diabetes mellitus (IDDM). After a 1-wk control... more
The metabolic effects of high-carbohydrate (70%), high-fiber (70 g) (HCHF) and low-carbohydrate (39%), low-fiber (10 g) (LCLF) diets were examined for 10 subjects with insulin-dependent diabetes mellitus (IDDM). After a 1-wk control period subjects on a metabolic ward were randomly allocated to HCHF or LCLF diets for 4 wk. After a 6-wk washout period subjects re-entered the metabolic ward for 4 wk on the alternate diet. Artificial-pancreas studies were performed on each diet for measurement of insulin requirements. Compared with the LCLF diet, the HCHF diet reduced basal insulin requirements (P less than 0.025), increased carbohydrate disposed of per unit insulin (P less than 0.0008), and lowered total (P less than 0.0004) and high-density-lipoprotein cholesterol (P less than 0.0013). Glycemic control and other lipid fractions did not differ significantly. These results suggest that in IDDM patients, HCHF diets enhance peripheral glucose disposal, decrease basal insulin requirements, and lower total cholesterol without altering glycemic control or triglycerides.
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The hypocholesterolemic effects of oat bran (OB) have been recently challenged. To carefully document the hypocholesterolemic effects of OB, 20 hypercholesterolemic men admitted to a metabolic ward were randomly allocated to either OB or... more
The hypocholesterolemic effects of oat bran (OB) have been recently challenged. To carefully document the hypocholesterolemic effects of OB, 20 hypercholesterolemic men admitted to a metabolic ward were randomly allocated to either OB or wheat bran (WB) for 21 d after a 7-d control-diet period. Control and treatment diets were designed to be identical in energy content and nutrients, differing only in the amount of soluble fiber. After 21 d, OB significantly decreased total cholesterol by 12.8% (P less than 0.001), low-density-lipoprotein cholesterol by 12.1% (P less than 0.004), and apolipoprotein B-100 by 13.7% (P less than 0.001) whereas WB had no significant effect. High-density-lipoprotein cholesterol and apolipoprotein A-I did not change significantly in either group. Serum triglycerides decreased by 10% in both groups but the decrease was only significant (P less than 0.04) in WB subjects. OB but not WB significantly reduced total cholesterol and other atherogenic lipoprotein fractions independent of other dietary changes.
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Preliminary selective blockade of micro, delta1, delta2, kappa1, and kappa2 opioid receptors proved to have no effect on the incidence of ventricular arrhythmias during a 10-min coronary occlusion and subsequent reperfusion in... more
Preliminary selective blockade of micro, delta1, delta2, kappa1, and kappa2 opioid receptors proved to have no effect on the incidence of ventricular arrhythmias during a 10-min coronary occlusion and subsequent reperfusion in ketamine-anesthetized rats. We propose that the endogenous opioid system has no considerable role in regulation of heart resistance to the arrhythmogenic effect of short-term local ischemia and subsequent reperfusion.
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Preliminary selective block of mu-, delta1-, delta2-, and kappa-opioid receptors had no effect on the incidence of ventricular arrhythmias during 10-min coronary occlusion-reperfusion in ketamine-narcotized rats. Repetitive short-term... more
Preliminary selective block of mu-, delta1-, delta2-, and kappa-opioid receptors had no effect on the incidence of ventricular arrhythmias during 10-min coronary occlusion-reperfusion in ketamine-narcotized rats. Repetitive short-term immobilization of rats for 2 weeks improved heart resistance to the arrhythmogenic action of coronary occlusion and reperfusion. Selective mu-opioid receptor antagonist CTAP completely abolished, while selective delta- and kappa-opioid receptor antagonists did not modulate the antiarrhythmic effect of adaptation. Probably, endogenous agonists of mu-opioid receptors play an important role in the adaptive improvement of heart resistance to arrhythmogenic factors, but are insignificant for the modulation of heart resistance to the arrhythmogenic action of short-term local ischemia-reperfusion in non-adapted animals.
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... James W Anderson, Susan Ridded/-Lawrence, Tammy L Floore, ... Breakfast 53 g Egg 33 g Egg 47 g Light bread 28 g Biscuits l8gMargarine 70gWaffies 13 g Jelly 7 g Margarine 241 g Juice 5 1 g Light syrup 226 g 2% Milk 118 g 2% Milk 1.5 g... more
... James W Anderson, Susan Ridded/-Lawrence, Tammy L Floore, ... Breakfast 53 g Egg 33 g Egg 47 g Light bread 28 g Biscuits l8gMargarine 70gWaffies 13 g Jelly 7 g Margarine 241 g Juice 5 1 g Light syrup 226 g 2% Milk 118 g 2% Milk 1.5 g Instant coffee 1.5 g Instant coffee ...
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ABSTRACT Export Date: 18 October 2014
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It is shown that prestimulation of cardiac delta-opioid receptors (OR) by selective agonists (DPDPE and TAN-67) decreases creatine kinase levels in the coronary effluent of isolated rat heart during 45-min global ischemia and 30-min... more
It is shown that prestimulation of cardiac delta-opioid receptors (OR) by selective agonists (DPDPE and TAN-67) decreases creatine kinase levels in the coronary effluent of isolated rat heart during 45-min global ischemia and 30-min reperfusion. This effect was completely abolished by pretreatment with a delta-antagonist naltrindole or a non-selective agonist naloxone. It was found that preactivation of cardiac delta-OR exacerbates reperfusion contractility dysfunction of the heart. This effect was also eliminated by opioid receptor antagonists. It is suggested that stimulation of cardiac delta-OR prevents irreversible cardiac cell damage but exacerbates contractility dysfunction during ischemia and reperfusion in vitro.
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Hibernation and its relevant potentials development of organ preservation techniques surgical technique for multiple organ preservation using hibernation induction trigger in multiple organ preservation extension of tissue survival time... more
Hibernation and its relevant potentials development of organ preservation techniques surgical technique for multiple organ preservation using hibernation induction trigger in multiple organ preservation extension of tissue survival time using delta opioid (DADLE) using hibernation induction trigger in hypothermic heart storage.
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Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24 h)... more
Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24 h) of rats induced the state which is similar TS in human: contracture damage of myofibrils, elevation of the serum creatine kinase MB level, increased 99mTc-pyrophosphate (99mTc-PYP) accumulation in the heart, QTc interval prolongation, and contractility dysfunction of the heart. Immobilization stress resulted in an increase in coronary blood flow. Emotional stress increased the serum catecholamine level. Blockade of β1-adrenergic receptor (AR) prevented stress-induced cardiac injury (SICI). Blockade of β2-AR aggravated stress-induced cardiac injury. Stimulation of β2-AR increased cardiac tolerance to stress. Inhibition of β3-AR, α1-AR had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravated SICI. Pretreatment with the selective β1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction, but recovery of cardiac contractility is not complete. There is indirect evidence that circulating catecholamines play an important role in SICI. Consequently, the activation of β1-AR plays a significant role in SICI. However, there are other receptors which are also involved in SICI and require further investigation.
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Opioid receptor agonists are involved in ischemic preconditioning and natural hibernation. The aim of this study was to determine whether pretreatment with D-Ala2-Leu5-enkephalin or morphine confers cardioprotection in large mammalian... more
Opioid receptor agonists are involved in ischemic preconditioning and natural hibernation. The aim of this study was to determine whether pretreatment with D-Ala2-Leu5-enkephalin or morphine confers cardioprotection in large mammalian hearts. We assessed myocardial functional recovery and global energy metabolism after ischemic cold storage. After pretreatment with D-Ala2-Leu5-enkephalin, morphine sulfate, or saline (n = 6 each), swine hearts were excised and stored for 75 minutes at 4 degrees C, then reperfused in a four-chamber isolated working heart apparatus. Serial myocardial biopsies were performed to assess cellular energy metabolism. Improved systolic (cardiac output, contractility) and diastolic (tau) left ventricular functions were observed in hearts pretreated with D-Ala2-Leu5-enkephalin or morphine. These benefits were not correlated with changes in high-energy phosphate levels. Cardiac enzyme leakage (creatine kinase, troponin-I) was similar among treated and control groups. Lactate efflux increased significantly in controls, but not in opioid-pretreated hearts (p &lt; 0.01) at 75 minutes of reperfusion. D-Ala2-Leu5-enkephalin and morphine pretreatments improve postischemic function after cold storage of swine hearts. Postischemic lactate reduction, but not high-energy phosphate levels, may account for the observed cardioprotective effects.
Research Interests: Creatine, Medicine, Energy Metabolism, Internal Medicine, Animals, and 15 moreCardioprotection, Creatine Kinase, Morphine, Enzyme, Clinical Sciences, Myocardium, Cardiac Output Monitoring, Cold Storage, Left Ventricular Function, High energy, Ischemic Preconditioning, Control Group, Contractility, Cardiac output, and Cardiovascular medicine and haematology
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We assessed the ability of a hibernation‐like delta2 specific opioid, Deltorphin‐Dvariant (Delt‐Dvar) to provide ischemic protection in a pig model of cardiopulmonary bypass (CPB). Cardiogenic shock is induced by decreasing CPB flow 50%... more
We assessed the ability of a hibernation‐like delta2 specific opioid, Deltorphin‐Dvariant (Delt‐Dvar) to provide ischemic protection in a pig model of cardiopulmonary bypass (CPB). Cardiogenic shock is induced by decreasing CPB flow 50% from baseline levels of 75–80 ml/kg/min to 37–40 ml/kg/min for 30 min and measuring the amount of lactic acid (LA). The CP circulation of a control and test pig weighing 75–85 kg was surgically diverted to an extracorporeal CPB circuit consisting of: Medtronic Affinity Oxygenator and integral hard shell venous reservoir, and a Medtronic affinity arterial blood filter. The test animal received Delt‐Dvar at a conc of 1.43 mg/kg in 30 ml physiological saline while the control received 30 ml physiological saline following 15 min of baseline CPB. This was followed by a 50% reduction in CPB flow for 30 min to 37–40 ml/kg/min, a flow rate mimicking cardiogenic shock. LA were measured as indicators of a switch to compensatory anaerobic metabolism. In Delt‐Dvar animal arterial LA dropped from 5.6 to 4.9 after 30 min of CPB flow at 50% and LA remained at 4.8 (a 30% reduction in LA) at 30 min after resumption of 100% CPB flow. In the control animal baseline LA of 2.8 increased to 6.0 at 30 min of 50% CPB flow and was 8.2 (a 292% increase in LA) 30 min after resumption of 100% CPB flow. This study indicates that Delt‐Dvar can markedly attenuate the onset of anaerobic metabolism in the face of profound ischemia.
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It has been established that pretreatment with the selective mu-opioid receptor (OR) agonist DALDA (0.1 mg/kg, i.v.) or the selective delta1-OR agonists DPDPE (0.09 mg/kg) and/or (-)-TAN-67 (0.08 mg/kg) has no effect on the incidence of... more
It has been established that pretreatment with the selective mu-opioid receptor (OR) agonist DALDA (0.1 mg/kg, i.v.) or the selective delta1-OR agonists DPDPE (0.09 mg/kg) and/or (-)-TAN-67 (0.08 mg/kg) has no effect on the incidence of ventricular arrhythmias induced by a 10-min coronary artery occlusion and a 10-min reperfusion in ketamine-anesthetized rats. In contrast, the pretreatment with the selective delta2-OR agonist deltorphin II (0.12 mg/kg) and the proposed delta2-OR agonists deltorphin D (0.3 mg/kg) and/or dermorphin H (0.23 mg/kg) increases cardiac resistance to the arrhythmogenic action of acute ischemia and reperfusion. Administration of the mixed mu- and delta-OR agonist dalargin (0.12 mg/kg) 15 min before the coronary artery ligation abolished only the reperfusive ventricular fibrillation. It is concluded that peptidergic stimulation of delta2-ORs can be used as a new means of increasing cardiac tolerance to the arrhythmogenic effects of acute ischemia and reperfusion.
Research Interests: Medicine, Internal Medicine, Animals, Male, Rats, and 3 moreWistar Rats, Ventricular Fibrillation, and Agonist
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ABSTRACT Epidemiologic studies indicate that dietary plant fats are negatively and dietary cholesterol positively correlated with the incidence of cardiovascular disease. However, recent research suggests that unsaturated fats may be... more
ABSTRACT Epidemiologic studies indicate that dietary plant fats are negatively and dietary cholesterol positively correlated with the incidence of cardiovascular disease. However, recent research suggests that unsaturated fats may be atherogenic because of their contribution to cellular oxidative stress and that cholesterol may exhibit antioxidant properties. To test this hypothesis, rabbits were fed diets containing 2 g corn oil/100 g diet, supplemented either with 16 g/100 g diet of corn oil (CO) or CO plus added cholesterol (CO+C) for 10 weeks. The cholesterol concentration in the CO+C diet was less than 30 mg cholesterol/100 g diet, which was sufficient to cause a significant rise in plasma and LDL cholesterol, but that did not lead to any detectable fatty steak or lesion formation. Compared with the native CO group, lipid hydroperoxide levels were significantly lower in both native lipoproteins (VLDLLDL) and lipolyzed remnants of this lipoprotein mixture derived from rabbits fed CO+C. This may be attributable in part to the observed decrease in unsaturated fatty acids as a result of dietary cholesterol supplementation. Relative to native lipoproteins, endothelial cells exposed to lipolyzed lipoprotein remnants experienced a significant increase in oxidative stress, as evidenced by increased DCF fluorescence, NF-ϰB, an oxidative stress sensitive transcription factor, was markedly induced in cells treated with both native and lipolyzed lipoproteins derived from the CO group, compared to the CO+C group. Independent of lipolysis, oxidative stress was markedly decreased in cells exposed to lipoproteins derived from animals fed CO+C, Furthermore, dietary cholesterol supplementation protected endothelial cells against lipolytic remnant-mediated barrier dysfunction. These data continue to support the hypothesis that lipolytic lipoprotein remnants are atherogenic and that small amounts of supplemental cholesterol may provide antioxidant protection.
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:It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis,... more
:It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis, necroptosis, apoptosis, and possibly autophagy, pyroptosis and ferroptosis. It has also been demonstrated that the NLRP3 inflammasome is involved in RI of the heart. An increase in adrenergic system activity during the restoration of coronary perfusion negatively affected cardiac resistance to RI. Toll-like receptors are involved in RI of the heart. Angiotensin II and endothelin-1 aggravated ischemic/reperfusion injury of the heart. Activation of neutrophils, monocytes, CD4+ T-cells and platelets contributes to cardiac ischemia/reperfusion injury. Our review outlines the role of these factors in reperfusion cardiac injury.
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Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and δ2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in... more
Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and δ2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in isolated rat heart. In this study, we hypothesize that this cardioprotective effect of CNH is mediated by activation of µ and δ2 ORs and preservation of mitochondrial function. Hearts from rats adapted to CNH (12 % oxygen) for 3 weeks were extracted, perfused in the Langendorff mode and subjected to 45 min of global ischemia and 30 min of reperfusion. Intervention groups were pretreated for 10 min with antagonists for different OR types: naloxone (300 nmol/l), the selective δ OR antagonist TIPP(ψ) (30 nmol/l), the selective δ1 OR antagonist BNTX (1 nmol/l), the selective δ2 OR antagonist naltriben (1 nmol/l), the selective peptide μ OR antagonist CTAP (100 nmol/l) and the selective κ OR antagonist nor-binaltorphimine (3 nmol/l). Creatine kinase activ...
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The role of opioid κ1 and κ2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid κ receptor agonists were administered... more
The role of opioid κ1 and κ2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid κ receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 – 48 % in untreated rats. Administration of the opioid κ1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42 %. Administration of the opioid κ receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41 %. The non-selective opioid κ receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid κ receptor, the peripherally acting opioid κ receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid κ2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally ac...
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The objectives of this study were to investigate the role of endogenous opioids in the mediation of stress-induced cardiomyopathy (SIC), and to evaluate which opioid receptors regulate heart resistance to immobilization stress. Wistar... more
The objectives of this study were to investigate the role of endogenous opioids in the mediation of stress-induced cardiomyopathy (SIC), and to evaluate which opioid receptors regulate heart resistance to immobilization stress. Wistar rats were subjected to 24 h immobilization stress. Stress-induced heart injury was assessed by 99mTc-pyrophosphate accumulation in the heart. The opioid receptor (OR) antagonists (naltrexone, NxMB – naltrexone methyl bromide, MR 2266, ICI 174.864) and agonists (DALDA, DAMGO, DSLET, U-50,488) were administered intraperitoneally prior to immobilization and 12 h after the start of stress. In addition, the selective µ OR agonists PL017 and DAMGO were administered intracerebroventricularly prior to stress. Finally pretreatment with guanethidine was used. Naltrexone did not alter the cardiac 99mTc-PP accumulation in stressed rats. NxMB aggravated stress-induced cardiomyopathy (P=0.005) (SIC). The selective µ OR agonist DALDA, which does not cross the blood-b...
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The hypothetical trigger of remote postconditioning (RPost) of the heart is the highmolecular weight hydrophobic peptide(s). Nitric oxide and adenosine serve as intermediaries between the peptide and intracellular structures. The role of... more
The hypothetical trigger of remote postconditioning (RPost) of the heart is the highmolecular weight hydrophobic peptide(s). Nitric oxide and adenosine serve as intermediaries between the peptide and intracellular structures. The role of the autonomic nervous system in RPost requires further study. In signaling mechanism RPost, kinases are involved: protein kinase C, PI3, Akt, JAK. The hypothetical end effector of RPost is aldehyde dehydrogenase-2, the transcription factors STAT, Nrf2, and also the BKCa channel.
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Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The... more
Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of ...
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Studies have shown that plasma albumin fractions (PAFs) from hibernating mammals can inhibit induced contractility of the guinea pig ileum similarly to morphine. This study examined PAFs from two species of prairie dogs, one that... more
Studies have shown that plasma albumin fractions (PAFs) from hibernating mammals can inhibit induced contractility of the guinea pig ileum similarly to morphine. This study examined PAFs from two species of prairie dogs, one that undergoes natural seasonal hibernation (white-tailed, WT) and one that does not but can be induced to hibernate (black-tailed, BT). Dose-response curves of lyophilized PAF yielded IC50 values (mg) of 20.23 for summer WT, 15.53 for hibernating WT, 15.45 for summer BT, and 13.16 for winter-active BT. Winter samples from both species have IC50s lower than samples from summer animals, indicating greater potency of winter PAFs in suppressing guinea pig ileum contractility and therefore the presence of more opioid ligands in winter prairie dog plasma. Studies to elucidate receptor selectivity of PAF continue.