Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage

Background: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone.

Methods: After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 [mu]m bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4[degrees]C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured.

Results: All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline.     

Effects of supplemental L-arginine during warm blood cardioplegia.

OBJECTIVES: Effects of supplemental L-arginine, nitric oxide precursor, during warm blood cardioplegia were assessed in the blood perfused isolated rat heart. METHODS: The isolated hearts were perfused with blood at 37 degrees C from a support rat. After 20 minutes of aerobic perfusion, the hearts were arrested for 60 minutes with warm blood cardioplegia given at 20-minute intervals. This was followed by 60 minutes of reperfusion. The hearts were divided into the following three groups according to the supplemental drugs added to the cardioplegic solution. The control group (n = 10) received standard warm blood cardioplegia. The L-ARG group (n = 10) received warm blood cardioplegia supplemented with L-arginine (3 mmol/l). The L-NAME group (n = 10) received warm blood cardioplegia supplemented with L-arginine (3 mmol/l) and L-nitro-arginine methyl ester, a competitive inhibitor of nitric oxide synthase (1 mmol/l). After 60 minutes of cardioplegic arrest, cardiac function, myocardial metabolism and myocardial release of circulating adhesion molecules were measured during reperfusion. RESULTS: Left ventricular end-diastolic pressure was significantly lower (p<0.05) in the L-ARG group than in the control group and the L-NAME group during reperfusion. Isovolumic left ventricular developed pressure, dp/dt and coronary blood flow were significantly greater (p< 0.05) in the L-ARG group during reperfusion. The L-ARG group resulted in early recovery of lactate metabolism during reperfusion. Myocardial release of circulating intercellular adhesion molecule-1 (ICAM-1) and E-selectin were significantly less (p<0.05) in the L-ARG group at 15 minutes of reperfusion. CONCLUSIONS: The results suggest that augmented nitric oxide by adding L-arginine to warm blood cardioplegia can preserve left ventricular function and ameliorate endothelial inflammation. The technique can be a novel cardioprotective strategy in patients undergoing cardiac surgery.     

Experimental myocardial preservation study of adding perfluorochemicals (FC43) in lidocaine cardioplegia.

OBJECTIVE: Lidocaine exhibits a cardioplegic action via acute inhibition of sodium influx into the myocardial cells. In terms of the cardiac function and calcium dynamics in the myocardial cells, we investigated the myocardial protective effect of addition of FC43 of Perfluorochemicals, which has an excellent oxygen transport function to meet the myocardial oxygen demand, on lidocaine-induced cardioplegia. METHODS: Isolated rat hearts were perfused with Langendorff mode and were divided to three experimental groups. During of preservation, these hearts were perfused continuously with the next three solution, potassium chloride was added to Krebs-Henseleit bicarbonate buffer to make potassium concentration of 20 mM in the first group (Group A), 2 mM lidocaine was added to Krebs-Henseleit bicarbonate buffer in the second group (Group B), and 2 mM lidocaine and 20% FC43 were added to Krebs-Henseleit bicarbonate buffer in the third group (Group C). After 60 minutes of continuous perfusion, the cardiac function and the intracellular calcium concentration in Groups A and B during cardioplegia were measured. Furthermore, after 360 minutes of continuous coronary perfusion, the cardiac function were measured in Group B and Group C. RESULTS AND CONCLUSIONS: Lidocaine cardioplegia showed a good recovery of cardiac function, because lidocaine induced prompt cardiac arrest by blocking sodium influx and inhibited the intracellular calcium overload by the following inhibition of sodium-calcium channels. Moreover, our results suggested that combining Perfluorochemicals with lidocaine produced a more effective myocardial-preservation that meets the myocardial oxygen demand during long-term cardiac arrest.     

Protectant activity of defibrotide in cardioplegia followed by ischemia/reperfusion injury in the isolated rat heart

BACKGROUND: Previous studies have shown that defibrotide, a polydeoxyribonucleotide obtained by depolymerization of DNA from porcine tissues, has important protective effects on myocardial ischemia, which may be associated with a prostacyclin-related mechanism. The purpose of this study was to investigate the direct effects of defibrotide (given in cardioplegia or after ischemia) on a model of rat heart recovery after cardioplegia followed by ischemia/reperfusion injury. METHODS: Isolated rat hearts, undergoing 5 minutes of warm cardioplegic arrest followed by 20 minutes of global ischemia and 30 minutes of reperfusion, were studied using the modified Langendorff model. The cardioplegia consisted of St. Thomas' Hospital solution augmented with defibrotide (50, 100, and 200 microg/mL) or without defibrotide (controls). Left ventricular mechanical function and the levels of creatine kinase, lactate dehydrogenase, and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha; the stable metabolite of prostacyclin) were measured during preischemic and reperfusion periods. RESULTS: After global ischemia, hearts receiving defibrotide in the cardioplegic solution (n = 8) manifested in a concentration-dependent fashion lower left ventricular end-diastolic pressure (p < 0.001), higher left ventricular developed pressure (p < 0.01), and lower coronary perfusion pressure (p < 0.001) compared to the control group. After reperfusion, hearts receiving defibrotide in the cardioplegic solution also had, in a dose-dependent way, lower levels of creatine-kinase (p < 0.01), lactate dehydrogenase (p < 0.001), and higher levels of 6-keto-PGF1alpha (p < 0.001) compared to the control group. Furthermore, when defibrotide was given alone to the hearts at the beginning of reperfusion (n = 7), the recovery of postischemic left ventricular function was inferior (p < 0.05) to that obtained when defibrotide was given in cardioplegia. CONCLUSIONS: Defibrotide confers to conventional crystalloid cardioplegia a potent concentration-dependent protective effect on the recovery of isolated rat heart undergoing ischemia/reperfusion injury. The low cost and the absence of contraindications (cardiac toxicity and hemodynamic effects) make defibrotide a promising augmentation to cardioplegia.     

Myocardial preservation in neonatal lambs. Comparison of hypothermia with crystalloid and blood cardioplegia

Low cardiac output after surgically induced myocardial ischemia is a major contributor to mortality and morbidity after operations for congenital heart defects, despite myocardial "protection" with the techniques of hypothermia and cardioplegia that have been effective in protecting mature myocardium. The purpose of this study was to investigate the effectiveness of topical cooling to 15 degrees C, crystalloid cardioplegia, and blood cardioplegia in protecting 28 isolated neonatal lamb hearts subjected to 2 hours of ischemia. Seven hearts were isolated and perfused in a similar manner with cooling to 15 degrees C but were then rewarmed without any ischemia to serve as a control group. All three groups (topical cooling, crystalloid cardioplegia, and blood cardioplegia) had recovery of systolic function (as measured by maximum developed pressure, maximum rate of pressure rise, peak developed pressure at a fixed volume, and peak rate of pressure rise at a fixed volume) equal to the control group; the exception was peak rate of pressure rise at a fixed volume in the blood cardioplegia group, in which recovery was worse than in the control group. No differences among three ischemia groups or in comparison with the control group were found for measures of diastolic function (ventricular diastolic pressure at a fixed volume or stiffness constant kA). Systolic function declined in all groups (including control) from baseline to the end of the experiment. These findings suggest that hypothermia exerted the dominant protective effect in these normal neonatal lamb hearts and there was no added protection from either crystalloid or blood cardioplegia.     

Effects of angiotensin-converting enzyme inhibitor during warm blood cardioplegia

BACKGROUND: Effects of captopril, an angiotensin-converting enzyme inhibitor, during warm blood cardioplegia were assessed in the blood-perfused, isolated rat heart. METHODS: The isolated hearts were arrested for 60 minutes with warm blood cardioplegia given at 20-minute intervals and were reperfused for 60 minutes. The control group (n = 10) received standard cardioplegia and the captopril group (n = 10) received cardioplegia supplemented with captopril (2 mmol/L). Cardiac function, myocardial metabolism, and cardiac release of circulating adhesion molecules were assessed before and after cardioplegic arrest. RESULTS: Left ventricular end-diastolic pressure and -dp/dt were significantly (p<0.05) lower and coronary blood flow was significantly (p<0.05) greater in the captopril group than the control group during reperfusion. The captopril group resulted in significantly (p<0.05) less cardiac release of lactate, thiobarbituric acid reactive substances during reperfusion. Cardiac release of intercellular adhesion molecule-1 was significantly (p<0.05) less in the captopril group at 60 minutes of reperfusion. CONCLUSIONS: The results suggest that supplementation of captopril during warm blood cardioplegia provides superior myocardial protection by suppressing lipid peroxidation and leukocyte-endothelial cell interaction during reperfusion.     

Cardiac function and myocardial performance of 24-hour-preserved asphyxiated canine hearts.

A method of 24-hour storage of asphyxiated canine hearts for orthotopic cardiac transplantation was studied to expand the geographical size of the donor pool. Left ventricular function of asphyxiated hearts preserved for 24 hours (group 1, n = 8) was compared with that of hearts donated on-site (group 2, n = 5). Group 1 donors were pretreated with verapamil hydrochloride, propranolol hydrochloride, and prostacyclin. The donor hearts were perfused with warm blood cardioplegia in situ after 10 minutes of asphyxiation and then perfused with cold crystalloid cardioplegia for 2 hours. The hearts were excised and stored in ice-cold University of Wisconsin solution for 22 hours. At orthotopic transplantation, coronary perfusion with warm blood cardioplegia was performed before the graft aorta was unclamped. Conventional cardiac variables (eg, cardiac output and maximum rate of rise of left ventricular pressure), myocardial performance, and diastolic compliance of grafted hearts were assessed 1 hour after weaning from bypass. All recipients in both groups were easily weaned from cardiopulmonary bypass without inotropic agents, and there were no significant differences in cardiac variables between the two groups. These results strongly suggest that cadaver hearts can be preserved for 24 hours with satisfactory cardiac function.     

Hemodynamic and Cardiac Electrophysiologic Effects of Lidocaine-Bupivacaine Mixture in Anesthetized and Ventilated Piglets

Background: The sensory blockade induced by a lidocaine-bupivacaine mixture combines the faster onset of lidocaine and the longer duration of bupivacaine. The current study compared the effects of large doses lidocaine (16 mg/kg), bupivacaine (4 mg/kg), and a mixture of 16 mg/kg lidocaine-4 mg/kg bupivacaine on hemodynamic and cardiac electrophysiologic parameters in anesthetized and ventilated piglets.

Methods: After carotid artery cannulation, a double micromanometer measured mean aortic pressure, left ventricular end diastolic pressure, and the first derivative of left ventricular pressure. Electrocardiogram recording and a bipolar electrode catheter measured RR, PQ, QRS, QTc, JTc, AH, and HV intervals. Lidocaine, bupivacaine, or the mixture was administered intravenously over 30 s, and studied parameters were measured throughout 30 min.

Results: Mean aortic pressure decreased in all groups (P < 0.05). The first derivative of left ventricular pressure was decreased in all groups (P < 0.001) but to a greater extent with the mixture compared with lidocaine (P < 0.04). RR, QTc, and JTc intervals were similarly increased in all groups (P < 0.05). In all groups, PQ, AH, HV, and QRS intervals were widened (P < 0.001). The lengthening of PQ was greater with bupivacaine (P < 0.02). The lengthening of AH was greater and delayed with bupivacaine compared with lidocaine (P < 0.03). The lengthening of HV and the widening of QRS were greater and delayed with bupivacaine (P < 0.01). The widening of QRS was greater with the mixture than with lidocaine (P < 0.01).     

Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart

BACKGROUND AND OBJECTIVES: Infusion of a lipid emulsion has been advocated for treatment of severe bupivacaine cardiac toxicity. The mechanism of lipid rescue is unknown. These studies address the possibility that lipid infusion reduces cardiac bupivacaine content in the context of cardiac toxicity. METHODS: We compared the effects of a 1% lipid emulsion with standard Krebs buffer after inducing asystole in isolated rat heart with 500 micromol/L bupivacaine. We compared times to first heart beat and recovery of 90% of baseline rate pressure product (RPP = heart rate x [left ventricular systolic pressure - left ventricular diastolic pressure]) between controls and hearts receiving 1% lipid immediately after bupivacaine. We also used minibiopsies to compare control bupivacaine tissue content with hearts getting lipid immediately after an infusion of radiolabeled bupivacaine. We then compared bupivacaine efflux from hearts with and without lipid infusion started 75 seconds after radiolabeled bupivacaine was administered. RESULTS: Infusion of lipid resulted in more rapid return of spontaneous contractions and full recovery of cardiac function. Average (+/- SEM) times to first beat and to 90% recovery of rate pressure product were 44.6 +/- 3.5 versus 63.8 +/- 4.3 seconds (P < .01) and 124.7 +/- 12.4 versus 219.8 +/- 25.6 seconds (P < .01) for lipid and controls, respectively. Lipid treatment resulted in more rapid loss of bupivacaine from heart tissue (P < .0016). Late lipid infusion, 75 seconds after bupivacaine infusion ended, increased the release of bupivacaine measured in effluent for the first 15-second interval compared with controls (183 vs. 121 nmol, n = 5 for both groups, P < .008). CONCLUSIONS: Lipid emulsion speeds loss of bupivacaine from cardiac tissue while accelerating recovery from bupivacaine-induced asystole. These findings are consistent with the hypothesis that bupivacaine partitions into the emulsion and supports the concept of a "lipid sink." However, the data do not exclude other possible mechanisms of action.     

Hemodynamic and cardiac electrophysiologic effects of lidocaine-bupivacaine mixture in anesthetized and ventilated piglets

BACKGROUND: The sensory blockade induced by a lidocaine-bupivacaine mixture combines the faster onset of lidocaine and the longer duration of bupivacaine. The current study compared the effects of large doses lidocaine (16 mg/kg), bupivacaine (4 mg/kg), and a mixture of 16 mg/kg lidocaine-4 mg/kg bupivacaine on hemodynamic and cardiac electrophysiologic parameters in anesthetized and ventilated piglets. METHODS: After carotid artery cannulation, a double micromanometer measured mean aortic pressure, left ventricular end diastolic pressure, and the first derivative of left ventricular pressure. Electrocardiogram recording and a bipolar electrode catheter measured RR, PQ, QRS, QT C, JT C, AH, and HV intervals. Lidocaine, bupivacaine, or the mixture was administered intravenously over 30 s, and studied parameters were measured throughout 30 min. RESULTS: Mean aortic pressure decreased in all groups ( P < 0.05). The first derivative of left ventricular pressure was decreased in all groups ( P < 0.001) but to a greater extent with the mixture compared with lidocaine ( P < 0.04). RR, QT C, and JT C intervals were similarly increased in all groups ( P < 0.05). In all groups, PQ, AH, HV, and QRS intervals were widened ( P < 0.001). The lengthening of PQ was greater with bupivacaine ( P < 0.02). The lengthening of AH was greater and delayed with bupivacaine compared with lidocaine ( P < 0.03). The lengthening of HV and the widening of QRS were greater and delayed with bupivacaine ( P < 0.01). The widening of QRS was greater with the mixture than with lidocaine ( P < 0.01). CONCLUSIONS: The alterations of ventricular conduction parameters are greater with 4 mg/kg bupivacaine than with a mixture of 16 mg/kg lidocaine-4 mg/kg bupivacaine, whereas the hemodynamic parameters are similarly altered.     

Influence of pre-existing ischemia on recovery from chemical cardioplegia. A study on pig hearts in an isolated blood-perfused model.

The impact of prior cardiac ischemia on recovery from chemical cardioplegia was investigated in pig hearts. Group I hearts were subjected to 9-min normothermic ischemia before the start of chemical cardioplegia. After 180 min of induced cardiac arrest, all hearts were reperfused and monitored for 120 min in a blood-perfused Langendorff model. Consistent with left ventricular performance, myocardial oxygen uptake was significantly lower in group I than in the other hearts during the first 60 min of reperfusion. Lactate elimination was significantly higher in group I at the start of reperfusion, but showed no intergroup difference after 25 min. Nor was intergroup difference found in left ventricular end-diastolic pressure, total myocardial flow or glucose extraction fraction during reperfusion. The mitochondrial ultrastructure was identical in the two groups before chemical cardioplegia. During cardioplegia it deteriorated in group I but normalized in group II. During reperfusion these circumstances were reversed. Although precardioplegic ischemia thus significantly impaired left ventricular performance during early recovery, with corresponding effects on metabolism and ultrastructure, stable performance during reperfusion indicated that the ischemic injury did not worsen.     

Preclinical evaluation of coronary vascular function after cardioplegia with HTK and different antioxidant additives.

OBJECTIVE: Due to limited resources, improvement of preservation solutions is still of great importance in cardiac transplant surgery. New additives with antioxidant properties were tested with respect to coronary function of isolated rat hearts. METHODS: Bretschneider HTK solution containing none or an antioxidant additive (deferoxamine, trolox or LK 616) was used for 8h cold cardioplegia. After reperfusion with Krebs-Henseleit buffer (KHB), we assessed vascular dilator capacity (bradykinin, adenosine triphosphate, reactive hyperemia), myocardial function (left ventricular developed pressure, heart rate, oxygen consumption) and release of biochemical markers (aspartate aminotransferase, creatine kinase, lactate dehydrogenase, troponin, adenosine). RESULTS: Bradykinin- and adenosine triphosphate-induced vasodilations were largely reduced in hearts stored 8h in traditional HTK as compared to unstored controls. Storage in HTK+LK 616 significantly improved bradykinin-induced vasodilation. Vasodilation toward ATP was best preserved in hearts stored in HTK+deferoxamine. Deferoxamine and trolox, both improved reactive hyperaemic response during reperfusion. Left ventricular pressure development was significantly reduced after 8h cardioplegia, but no difference existed between different cardioplegia groups. Release of biochemical markers of tissue injury was similar in all cardioplegia groups. After storage in HTK+LK 616 (100 microM), however, heart marker release was slightly augmented as compared to HTK. CONCLUSIONS: Despite similar myocardial function and marker release, coronary vascular function after cardioplegic storage may profit by addition of iron chelators (or antioxidants) to traditional HTK solution.     

Arresting donor hearts with extracellular-type cardioplegia prevents vasoconstriction induced by UW solution.

The effects of arresting donor hearts with University of Wisconsin solution was investigated. Donor dogs were divided into two groups according to the technique used for arresting the heart. In group I (n = 6) the heart was arrested with University of Wisconsin solution, whereas in group II (n = 6) extracellular-type cardioplegia (K+ = 20 mmol/liter) was used to induce cardioplegic arrest. Aortic root pressure was measured during the infusion of solution at constant flow. In both groups, the hearts were then flushed and stored in cold University of Wisconsin solution for 6 h. The hearts were transplanted orthotopically and disconnected from cardiopulmonary bypass. Left ventricular function was evaluated by pressure-volume relations using a conductance catheter. Peak aortic root pressure during the infusion was significantly higher in group I than in group II, although post-transplant left ventricular function was similar in both groups. Although there was no difference in cardiac function after implantation, donor hearts should be arrested by extracellular-type cardioplegia to prevent coronary vasoconstriction associated with preservation in University of Wisconsin solution.     

The effect of bupivacaine on myocardial tissue hypoxia and acidosis during ventricular fibrillation

Previously we observed that during bupivacaine-induced circulatory collapse, myocardial tissue pH declined more slowly than expected. Here we evaluated the effect of bupivacaine on myocardial acidosis induced by ventricular fibrillation. Sixteen dogs were anesthetized with 1.5% end-tidal isoflurane, the chest was opened, and a probe that measured oxygen pressure (PmO(2)), carbon dioxide pressure, pH, and temperature was inserted into myocardial tissue. After baseline measures, each dog received either 10 mg/kg bupivacaine (n = 8) or a sham saline treatment (n = 8). Three minutes later ventricular fibrillation was initiated electrically, and the rate of change in PmO(2) and pH during ventricular fibrillation was measured. Baseline physiological measures were similar in the two groups of dogs. During ventricular fibrillation there was a rapid decrease in PmO(2), and the rate of decrease was not different between sham- and bupivacaine-treated dogs. Tissue pH decreased during ventricular fibrillation, and the rate of decrease was 4 times faster in sham- compared with bupivacaine-treated dogs (P < 0.05). These results show that bupivacaine attenuated myocardial tissue acidosis during ventricular fibrillation. This potentially beneficial effect may be a result of bupivacaine's ability to inhibit myocardial lactate and carbon dioxide production. This suggests a potential clinical application of bupivacaine for myocardial preservation. IMPLICATIONS: In this animal study pretreatment with bupivacaine attenuated the progression of myocardial acidosis during ventricular fibrillation. The dogs regained normal hemodynamic variables after lipid infusion. The findings suggest such that bupivacaine may protect the heart against ischemic acidosis.     

Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation

BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.     

Lidocaine-magnesium blood cardioplegia was equivalent to potassium blood cardioplegia in left ventricular function of canine heart

This study evaluated the effects of lidocaine-magnesium blood cardioplegia on left ventricular function compared with potassium blood cardioplegia. Crystalloid cardioplegia which contains lidocaine has been reported but blood cardioplegia is rare. Thirteen dogs received 60 min of global ischemia under hypothermic cardioplumonary bypass (30 degrees C). Potassium blood cardioplegia was administered every 20 min in group A (n=6), and lidocaine-magnesium blood cardioplegia in group B (n=7). We compared the ratio of Emax obtained during IVC occlusion at pre- and post-global ischemia (%Emax) and LVSW (%LVSV). Cardiac function was evaluated prior to CPB and 60 min after reperfusion. There was no difference in time required for cardiac arrest between the two groups (group A: 78+/-3 s, group B: 89+/-9 s). Percentage maximal elastance was significantly better in group B (group A: 63+/-3%, group B: 76+/-4%, P<0.05). Percentage tissue water content of the myocardium after CPB was significantly lower in group B (group A: 82.3+/-4%, group B: 75.5+/-2%, P<0.05). Lidocaine-magnesium blood cardioplegia was equivalent to potassium blood cardioplegia in systolic left ventricular function and reduced myocardial edema in canine heart.     

Cariporide对未成熟兔心肌缺血再灌注损伤的保护作用

目的　探讨甲磺酸苯甲酰胍类化合物Cariporide对未成熟兔心肌缺血再灌注损伤的保护作用及其机制。　方法　以离体灌注幼兔心脏为模型 ,将 2 4只幼兔心脏随机均分为对照组 (应用St.ThomasⅡ液 )和实验组 (应用Cariporide St .ThomasⅡ液 ) ,常温缺血 60min ,期间每 2 0min灌注 1次保护液 ,恢复灌注后 ,测定心率、心律、平均动脉压、冠脉流量、左心室收缩压、左心室舒张末压、左心室压力微分 (±dp/dt)和心肌酶。将另 6只幼兔的心肌单细胞悬液随机均分为基础 (未予缺氧处理 )、钙对照和钙实验组 (经缺氧、再复氧处理 ,钙实验组于缺氧时加入Cariporide 1μmol/L) ,用激光共聚焦显微镜测定心肌细胞内游离钙 ([Ca2 ]i)浓度 ,以钙荧光强度比值表示。　结果　与对照组相比 ,实验组缺血、再灌注后室颤发生率低 ,心肌酶漏出量少 ,平均动脉压、左心室收缩压、冠脉流量及±dp/dt均明显增加 ,左心室舒张压低。未成熟兔心肌细胞内 [Ca2 ]i浓度 ,钙实验组比钙对照组明显减少 (P <0 0 1) ,钙实验组与基础组差异无显著意义 (14 4 6± 12 8与 13 75± 10 2 ,P >0 0 5)。结论　Cariporide对未成熟心肌缺血再灌注损伤有保护作用 ,其机制是抑制心肌细胞内 [Ca2 ]i超载引起的缺血再灌注损伤     

Stereospecific Effect of Bupivacaine Isomers on Atrioventricular Conduction in the Isolated Perfused Guinea Pig Heart

Background: The local anesthetic bupivacaine is an equal mixture of two optically active isomers known to exert different cardiotoxic profiles in vivo. Enantiomer-specific forms of bupivacaine may have differential effects on cardiovascular function, specifically on cardiac electrophysiology. The authors' aim was to determine if there were any direct functional differences in the cardiac effects of bupivacaine isomers. The isolated heart was used to avoid possible indirect cardiac effects of bupivacaine, such as autonomic nervous and hormonal influences, as well as preload and afterload factors.

Methods: The hearts of 12 ketamine-anesthetized guinea pigs were perfused with Krebs-Ringer's solution (97% oxygen, 3% carbon dioxide) at constant perfusion pressure using the Langendorff technique. Atrial and ventricular bipolar electrodes were placed to measure heart rate (HR) and atrioventricular (AV) conduction time. Left ventricular pressure (LVP), coronary flow, and inflow and outflow oxygen tensions were also measured. Oxygen delivery, oxygen consumption (MVO2), and percentage of oxygen extraction were calculated. Each heart was perfused with increasing randomized concentrations (0.5, 1, 5, 10 micro Meter) of both isomers and the racemate of bupivacaine.

Results: Racemic and isomeric bupivacaine equally and dose dependently decreased cardiac function. At 10 micro Meter bupivacaine these changes were HR, -17 +/- 2%; LVP, -50 +/- 3%; coronary flow, -20 +/- 40%; and MVO2, -46 +/- 40%. The (+) isomer significantly prolonged AV conduction compared with the racemate and the (-) isomer at all concentrations. At 10 micro Meter, AV time was 54 +/- 6% longer with the (+) isomer and 30 +/- 4% longer with the (+/-) racemate than with the (-) isomer. The greater delay in AV time with the (+) than the racemate or (-) isomer led to a second-degree AV dissociation in 10 of 12 of hearts treated with (+) bupivacaine.     

Opioids confer myocardial tolerance to ischemia: interaction of delta opioid agonists and antagonists

BACKGROUND: Mammalian hibernation biology is now known to be mediated by delta opioids. The altered myocellular physiology of hibernation closely parallels that of hypothermic ischemia used to protect the heart for cardiac surgery. METHODS AND RESULTS: The present study examined the interaction of delta opioid agonists and antagonists on myocardial tolerance to ischemia. By means of a nonhibernating isolated rabbit heart model, functional and metabolic myocardial parameters were assessed during nonischemic baseline and postischemic recovery periods. Control hearts with standard cardioplegic protection alone were compared with those with cardioplegia plus preperfusion with a delta opioid agonist, a delta opioid antagonist, or both. All hearts were then subjected to 2 hours of global ischemia. Compared with cardioplegia alone, postischemic left ventricular developed pressure, coronary flows, and myocardial oxygen consumption were all increased with administration of delta opioid agonists and decreased below baseline with delta opioid antagonists. Functional recovery of left ventricular developed pressure was improved with opioids (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist: 65 +/- 5 mm Hg, P <.01) and inhibited with antagonists (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid antagonist: 17 +/- 5 mm Hg, P <.05), and true to form, the protective opioid effect was negated when combined with an antagonist (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist and delta opioid antagonist: 42 +/- 4 mm Hg, P = not significant). CONCLUSIONS: This study demonstrates that cardiac tolerance to ischemia may be mediated by delta opioids.     

Differences in Cardiotoxicity of Bupivacaine and Ropivacaine Are the Result of Physicochemical and Stereoselective Properties

Background: Ropivacaine is believed to have a lower incidence of clinical cardiac side effects than bupivacaine. The aim of this study was to compare the direct cardiac effects of the optically pure S (-)-ropivacaine isomer and its nonclinically used R (+)-isomer with both optically pure bupivacaine isomers in isolated hearts. The hypothesis was that differences in direct cardiac effects are distinguished not only by stereoselective actions of local anesthetic molecules to specific receptors, but also by physicochemical differences triggered by replacing the butyl- by a propyl-residual on pipecoloxylide.

Methods: Guinea pig hearts (n = 31) were excised and perfused by the Langendorff method. Atrial and ventricular bipolar electrodes were placed to measure heart rate and atrioventricular conduction time. Left ventricular pressure, coronary flow, and oxygen tensions were measured. Twelve hearts were perfused with increasing concentrations (0.5, 1.0, 5.0, and 10 [mu]m) of both isomers of bupivacaine, and 13 hearts were perfused with the same concentrations of ropivacaine isomers. Six hearts were perfused with higher concentrations (20, 30, 40, and 50 [mu]m) of both isomers of ropivacaine. The order of isomers and anesthetic chosen were randomized.

Results: Both anesthetics had negative inotropic and chronotropic effects without evidence of stereoselectivity. Equal concentrations of both isomers of bupivacaine had negative inotropic effects greater than that of ropivacaine isomers. Atrioventricular conduction time was prolonged by both anesthetics in a concentration-dependent manner, but bupivacaine isomers increased atrioventricular conduction time more than ropivacaine isomers. In contrast to other variables, atrioventricular conduction time showed evident stereoselectivity for bupivacaine at the lowest concentration (0.5 [mu]m) but only at higher concentrations for ropivacaine (> 30 [mu]m). The R (+)-isomer was more potent than the S (-)-isomer on increasing atrioventricular conduction time for both bupivacaine and ropivacaine.