Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart

Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml small middle dot min(-1) small middle dot grams wet wt(-1) and reperfusion. D[2-(3)H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury.     

Insulin-like growth factor-1 improves postischemic recovery in hypertrophied hearts.

BACKGROUND: Severe myocardial hypertrophy is associated with decreased tolerance to ischemia compared with normal hearts. We hypothesized that treatment with insulin-like growth factor-1 (IGF-1) improves postischemic myocardial recovery by increasing glucose uptake during ischemia and early reperfusion. METHODS: Banding of the thoracic aorta in 10-day-old rabbits created pressure-overload hypertrophy. At 5 weeks of age (severe hypertrophy), aortic banded and sham-operated isolated hearts underwent 30 minutes of normothermic ischemia with or without IGF-1 in the preischemic perfusate and cardioplegia followed by 30 minutes of reperfusion. RESULTS: 2-Deoxyglucose uptake (31P-NMR) and phosphatidylinositol-3-kinase (PI-3-kinase) activity were significantly lower in hypertrophied hearts. Insulin-like growth factor-1 restored glucose uptake and PI-3-kinase activity to control levels in the hypertrophied hearts and both effects were blocked by wortmannin (a PI-3-kinase inhibitor). Postischemic developed pressure was significantly improved in IGF-1-treated hearts compared with untreated or IGF-1+wortmannin-treated hypertrophied hearts. CONCLUSIONS: These data indicate that IGF-1 improves glucose uptake and tolerance to ischemia in hypertrophied hearts. Myocardial IGF-1 effects are likely mediated through a PI-3-kinase-dependent pathway.     

Amino acid substrate preloading and postischemic myocardial recovery.

During induced myocardial ischemia for cardiac surgery, myocardial stunning occurs and aerobic metabolism of glucose, fatty acids, and lactate is inhibited as anaerobic pathways predominate. Even following reperfusion, stunned myocardium uses oxygen and substrate inefficiently leading to poor functional recovery as less mechanical work is developed per oxygen utilized. Amino acids potentially can act as cardiac metabolic substrates during and after ischemia, utilizing the transamination of amino acids by the malate-aspartate shuttle to form high energy phosphates via the tricarboxylic acid cycle. We investigated if "preloading" hearts with a physiologic spectrum of amino acids could increase postischemic myocardial recovery. Isolated perfused rabbit hearts were subjected to 120 min of 34 degrees C cardioplegic ischemia. Hearts received cardioplegia alone as controls or were "preloaded" with a 0.05% amino acid perfusion for 30 min prior to cardioplegic ischemia. Following reperfusion, analysis of functional recovery revealed that contractility and cardiac efficiency were improved with amino acids substrate preloading. The mechanism of this may be due to uptake of amino acids prior to ischemia, which are later utilized for internal reparative work during ischemia and external contractile work after ischemia.     

Role of ceramide in ischemic preconditioning

BACKGROUND: A recent study showed increased myocardial content of ceramide and sphingosine during preconditioning (PC). Because sphingosine-1-phosphate, a metabolite of ceramide, may function as an antiapoptotic factor, we hypothesized the increased ceramide during PC may be heart's effort to harness its own protection. STUDY DESIGN: The isolated hearts were divided into five groups: 1) perfused for 3 hours 45 minutes with KHB buffer (control); 2) perfused with buffer for 45 minutes followed by 30 minutes of ischemia and 2 hours of reperfusion; 3) perfused for 15 minutes with desipramine followed by 30 minutes of perfusion with buffer, 30 minutes of ischemia, and 2 hours of reperfusion; 4) preconditioned followed by 30 minutes of ischemia and 2 hours of reperfusion; and 5) the same as 4), but preperfused for 15 minutes with desipramine. Myocardial preservation was assessed by examining left ventricular function, infarct size, and cardiomyocyte apoptosis. RESULTS: Ischemia/reperfusion-mediated cardiac dysfunction was partially restored with desipramine. PC improved postischemic ventricular recovery and reduced myocardial infarct size and cardiomyocyte apoptosis. The cardioprotective abilities of PC were abolished with desipramine, which also downregulated a PC-mediated increase in antiapoptotic protein Bcl-2. The apparent paradoxical results of desipramine can be explained by the increase in proapoptotic ceramide content in the ischemic reperfused heart that was blocked with desipramine and an increase in antiapoptotic sphingosine-1-p content in the preconditioned heart that was inhibited with desipramine. CONCLUSIONS: The results suggested for the first time that sphingolipid can induce the expression of Bcl-2 warranting its clinical use as a pharmacologic PC agent.     

Insulin improves functional and metabolic recovery of reperfused working rat heart

Background. Glucose, insulin, and potassium solution improves left ventricular function in refractory pump failure. Direct effects of insulin on the heart cannot be determined in vivo. We hypothesized that insulin has a direct positive inotropic effect on the reperfused heart.

Methods. Isolated working rat hearts were perfused with buffer containing glucose (5 mmol/L) plus oleate (1.2 mmol/L). Hearts were subjected to 15 minutes of ischemia and reperfused with or without insulin (100 μU/mL) for 40 minutes. Epinephrine (1 μmol/L) was added for the last 20 minutes.

Results. Hearts recovered 51.1% of preischemic cardiac power in the absence and 76.4% in the presence of insulin (p < 0.05). Whereas oleate oxidation remained unchanged, glucose uptake and oxidation increased during reperfusion with epinephrine (p < 0.01). This increase was significantly greater when hearts were reperfused in the presence of insulin (p < 0.01). Insulin also prevented an epinephrine-induced glycogen breakdown during reperfusion (p < 0.05).

Conclusions. Insulin has a direct positive inotropic effect on postischemic rat heart. This effect is additive to epinephrine and occurs without delay. Increased rates of glucose oxidation and net glycogen synthesis are more protracted.     

Enflurane enhances postischemic functional recovery in the isolated rat heart

Enflurane is a direct myocardial depressant and may act as a myocardial protective agent during ischemia. The authors studied the effects of enflurane on myocardial high-energy phosphates and tolerance to ischemia in the normothermic, isolated rat heart. After isolation and perfusion with Krebs-Henseleit buffer, the hearts were perfused with either buffer (control) or buffer gassed with 2% enflurane for 10 minutes. Thereafter, hearts were made globally ischemic and elapsed times to initiation of ischemic contracture (IC) were determined. ATP and creatine phosphate (CP) were measured at the conclusion of control and enflurane administration and at IC. Ten hearts per group were reperfused with buffer following IC for 20 min; peak pressure and ATP and CP were determined. Administration of 2% enflurane significantly decreased peak pressure by 20% but did not alter baseline high-energy phosphate levels nor did it prolong time to IC. However, enflurane-treated hearts exhibited significantly greater (P less than 0.01) recovery of function as defined by per cent return of peak pressure (67% +/- 3%) when compared with those hearts not treated with enflurane preischemically (44% +/- 5%). Also, enflurane-treated hearts had significantly higher (P less than 0.01) ATP levels at the conclusion of reperfusion than hearts not perfused with enflurane (12.2 +/- .8 mumol/g dry weight vs. 9.0 +/- 0.8 mumol/g dry weight). These findings suggest that enflurane administered prior to an ischemic interval enhances postischemic myocardial recovery.     

Diltiazem during reperfusion preserves high energy phosphates by protection of mitochondrial integrity.

OBJECTIVE: This study evaluates the effects of diltiazem administered during reperfusion on hemodynamic, metabolic, and ultrastructural postischemic outcome. METHODS: Hearts of 38 adult White New Zealand rabbits underwent 60 min of global cold ischemia followed by 40 min of reperfusion in an erythrocyte perfused isolated working heart model. Hearts were randomly assigned to four groups and received diltiazem (0.1, 0.25, and 0.5 micromol/l) during reperfusion only, or served as control. RESULTS: The postischemic time courses of heart rate, aortic flow, and external stroke work clearly reflected the dose-dependent negative chronotropic and inotropic efficacy of diltiazem in the two higher concentrations. High energy phosphates (HEP) determined from myocardial biopsies taken after 40 min of reperfusion were significantly better preserved in all treatment groups compared to control hearts. Similarly ultrastructural grading of mitochondria and myofilaments revealed a significant reduction of reperfusion injury in hearts that received diltiazem compared to control. CONCLUSIONS: Diltiazem protects mitochondrial integrity and function, thereby preserving myocardial HEP levels. Only low dose diltiazem (0.1 micromol/l) during reperfusion combines both, optimal mitochondrial preservation with minimal changes in hemodynamics.     

Promoting angiogenesis protects severely hypertrophied hearts from ischemic injury

BACKGROUND: Myocardial hypertrophy is associated with progressive contractile dysfunction, increased vulnerability to ischemia-reperfusion injury, and is, therefore, a risk factor in cardiac surgery. During the progression of hypertrophy, a mismatch develops between the number of capillaries and cardiomyocytes per unit area, suggesting an increase in diffusion distance and the potential for limited supply of oxygen and nutrients. We hypothesized that promoting angiogenesis in hypertrophied hearts increases microvascular density, thereby improves tissue perfusion and substrate availability, maintains myocardial function, and improves postischemic recovery. METHODS: Left ventricular hypertrophy was created in 10-day-old rabbits by aortic banding and progression was monitored by echocardiography. At 4 weeks (compensated hypertrophy), 2 microg of vascular endothelial growth factor (VEGF) or placebo was administered intrapericardially. After 2 weeks, microvascular density, coronary flow (CF), and glucose uptake (GU) were measured. Tolerance to ischemia was determined by cardiac function measurements before and after ischemia-reperfusion using an isolated heart preparation. RESULTS: Microvascular density increased significantly following VEGF treatment (1.43 +/- 0.08/nuclei/field vs 1.04 +/- 0.06/nuclei/field untreated hypertrophy). Concomitantly, there was an increase in CF (7 +/- 0.5 vs 5 +/- 0.4 mL/min/g) and GU (1.24 +/- 0.2 vs 0.69 +/- 0.2 micromoles/g/30 minutes; p 相似文献   

Is protection of ischemic neonatal myocardium by cardioplegia species dependent?

Hypothermia combined with pharmacologic cardioplegia protects the globally ischemic adult heart, but this benefit may not extend to children, resulting in poor postischemic recovery of function and increased mortality. The relative susceptibilities to ischemia modified by hypothermia alone and by hypothermia plus cardioplegia were assessed in isolated perfused neonatal (3- to 4-day-old) rabbit and pig hearts. Hearts were perfused aerobically with Krebs buffer solution in the working mode for 30 minutes and aortic flow was recorded. This was followed by 3 minutes of hypothermic (14 degrees C) coronary perfusion with either Krebs or St. Thomas' Hospital cardioplegic solution No. 2 followed by hypothermic (14 degrees C) global ischemia (rabbits 2, 4, and 6 hours; pigs 2 and 4 hours). Hearts were reperfused for 15 minutes in the Langendorff mode and 30 minutes in the working mode, and recovery of postischemic aortic flow was measured. Hypothermia alone provided excellent protection of the ischemic neonatal rabbit heart, with recovery of aortic flow after 2 and 4 hours of ischemia at 91% +/- 4% and 87% +/- 5% (mean +/- standard deviation) of its preischemic value. Recovery after 6 hours of ischemia was depressed to 58% +/- 9% of its preischemic value. Ischemic neonatal pig hearts protected with hypothermia alone recovered 94% +/- 3% of preischemic aortic flow after 2 hours; none was able to generate flow after 4 hours. St. Thomas' Hospital solution No. 2 decreased postischemic aortic flow after 4 hours of ischemia in rabbit hearts from 87% +/- 5% to 70% +/- 7% (p less than 0.05, hypothermia alone versus hypothermia plus cardioplegia) but improved postischemic recovery of aortic flow in pig hearts after 4 hours of ischemia from 0 to 73% +/- 13% (p less than 0.0001, hypothermia alone versus hypothermia plus cardioplegia). This effect was dose related in both species. We conclude that the neonatal pig heart is more susceptible to ischemia modified by hypothermia alone than the neonatal rabbit and that St. Thomas' Hospital solution No. 2 improves postischemic recovery of function in the neonatal pig but decreases it in the neonatal rabbit. This species-dependent protection of the neonatal heart may be related to differences in the extent of myocardial maturity at the time of study.     

Insulin-induced improvement of postischemic recovery is abolished by inhibition of protein kinase C in rat heart

OBJECTIVE: We demonstrated earlier that postischemic addition of insulin improves recovery of function in isolated rat heart by phosphatidylinositol 3-kinase. Activation of phosphatidylinositol 3-kinase before ischemia improves recovery of the heart after ischemia through protein kinase C. We tested whether protein kinase C activation is required for the positive inotropic effect of insulin during reperfusion. METHODS: Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing [2-(3)H]glucose (5 mmol/L, 0.05 microCi/mL) plus oleate (0.4 mmol/L) and were subjected to 15 minutes of global ischemia followed by 35 minutes of reperfusion with or without insulin (1 mU/mL). We measured cardiac power, glucose uptake, and tissue metabolites. The protein kinase C inhibitor chelerythrine (5 micromol/L) was added either at the beginning of the experiment or together with insulin. Experiments were repeated under normoxic conditions. RESULTS: Cardiac power before ischemia was 9.63 to 12.4 mW. Insulin improved recovery of power after ischemia (96.3% +/- 10.8% versus 65.7% +/- 3.79%, P <.05). This effect was abolished by chelerythrine (55.3% +/- 6.49%). However, chelerythrine given at reperfusion did not block insulin's effect on recovery (101.0% +/- 4.25%, P <.05). Postischemic glucose uptake was not increased by insulin (3.07 +/- 0.32 before, 3.45 +/- 0.34 micromol/min/gdw after ischemia, not significant) and was not affected by chelerythrine (3.01 +/- 0.26 before, 3.29 +/- 0.32 micromol/min/gdw after ischemia, not significant). Under normoxic conditions, chelerythrine did not influence insulin's effects on glucose uptake or power. CONCLUSION: The results suggest that (1) insulin's effect on recovery is dependent on ischemia-induced protein kinase C activation, (2) the activity of protein kinase C during reperfusion may not be important for this effect of insulin, and (3) protein kinase C plays no role in insulin's effect on glucose uptake under normoxic or postischemic conditions.     

Age-related changes in the ability of hypothermia and cardioplegia to protect ischemic rabbit myocardium

Hypothermia combined with pharmacologic cardioplegia protects the globally ischemic adult heart, but this benefit may not extend to children; poor postischemic recovery of function and increased mortality may result when this method of myocardial protection is used in children. The relative susceptibilities to ischemia-induced injury modified by hypothermia alone and by hypothermia plus cardioplegia were assessed in isolated perfused immature (7- to 10-day-old) and mature (6- to 24-month-old) rabbit hearts. Hearts were perfused aerobically with Krebs-Henseleit buffer in the working mode for 30 minutes, and aortic flow was recorded. This was followed by 3 minutes of hypothermic (14 degrees C) coronary perfusion with either Krebs or St. Thomas' Hospital cardioplegic solution No. 2, followed by hypothermic (14 degrees C) global ischemia (mature hearts 2 and 4 hours; immature hearts 2, 4, and 6 hours). Hearts were reperfused for 15 minutes in the Langendorff mode and 30 minutes in the working mode, and recovery of postischemic function was measured. Hypothermia alone provided excellent protection of the ischemic immature rabbit heart, with recovery of aortic flow after 2 and 4 hours of ischemia at 97% +/- 3% and 93% +/- 4% (mean +/- standard deviation) of the preischemic value. Mature hearts protected with hypothermia alone recovered only minimally, with 22% +/- 16% recovery of preischemic aortic flow after 2 hours; none were able to generate flow at 4 hours. St. Thomas' Hospital solution No. 2 improved postischemic recovery of aortic flow after 2 hours of ischemia in mature hearts from 22% +/- 16% to 65% +/- 6% (p less than 0.05), but actually decreased postischemic aortic flow in immature hearts from 97% +/- 3% to 86% +/- 10% (p less than 0.05). To investigate any dose-dependency of this effect, we subjected hearts from both age groups to reperfusion with either Krebs solution or St. Thomas' Hospital solution No. 2 for 3 minutes every 30 minutes throughout a 2-hour period of ischemia. Reexposure to Krebs solution during ischemia did not affect postischemic function in either age group. Reexposure of immature hearts to St. Thomas' Hospital solution No. 2 caused a decremental loss of postischemic function in contrast to incremental protection with multidose cardioplegia in the mature heart. We conclude that immature rabbit hearts are significantly more tolerant of ischemic injury than mature rabbit hearts and that, unexpectedly, St. Thomas' Hospital solution No. 2 damages immature rabbit hearts.     

Enhanced myocardial protection during global ischemia with 5'-nucleotidase inhibitors.

Depletion of adenosine triphosphate precursors, such as myocardial adenosine, during global ischemia results in poor postischemic adenosine triphosphate repletion and functional recovery. Neonatal hearts may be more resistant to this deleterious effect of ischemia, because they are characterized by low 5'-nucleotidase activity, which may result in higher sustained endogenous myocardial adenosine triphosphate precursor levels during ischemia. Adult hearts, however, have high levels of 5'-nucleotidase activity leading to depleted precursors during ischemia and poor postischemic functional recovery. Augmenting myocardial adenosine exogenously during ischemia in adult hearts has a beneficial effect on recovery. The present study tested if preservation of nucleotide precursors, better adenosine triphosphate repletion, and enhanced postischemic myocardial recovery in adult hearts could be achieved with a "neonatal" strategy. Therefore 5'-nucleotidase inhibitors were administered to isolated, perfused adult rabbit hearts subjected to 120 minutes of ischemia (at 34 degrees C) to determine if this improved functional recovery. Hearts received St. Thomas' Hospital cardioplegic solution (control hearts) or cardioplegic solution containing 5'-nucleotidase inhibitors: pentoxifylline, thioinosine, [s-(p-nitrophenyl)-4-thioinosine], or thioinosine's dimethyl sulfoxide vehicle alone. After ischemia and reperfusion, recovery of systolic function, diastolic function, and myocardial oxygen consumption was significantly better with 5'-nucleotidase inhibition. No changes in coronary flow were noted. We speculate and are pursuing the theory that the mechanism of 5'-nucleotidase inhibition's favorable action is due to preventing the catabolism, transport, and loss of nucleotide precursors during ischemia, maintaining adenosine triphosphate precursor availability.     

Differences in prolonged ischemia length using ischemic preconditioning in the rabbit heart. Tolerable limitation time for surgically induced myocardial ischemia during normothermic cardiac operation

BACKGROUND: To determine the effect of the tolerable limitation time of prolonged ischemia after ischemic preconditioning on postischemic functional recovery and infarct size reduction in the rabbit heart. METHODS: White rabbits (n=30) were used for Langendorff perfusion. Control hearts were perfused at 37 degrees C for 180 min; 30 min global ischemia hearts (30GI) received 30 min global ischemia and 120 min reperfusion; IPC+30GI hearts received 5 min zero flow global ischemia and 5 min reperfusion prior to 30 min global ischemia; 20 min global ischemia hearts (20GI) received 20 min global ischemia and 120 min reperfusion; IPC+20GI hearts received 5 min zero flow global ischemia and 5 min reperfusion prior to 20 min global ischemia. RESULTS: Infarct size in the 30GI hearts was 33.5+/-4.0% and 1.7+/-0.5% in the control hearts. The 20GI hearts and IPC+30GI hearts decreased infarct size, as compared with the 30GI hearts (13.0+/-1.8% and 16.6+/-1.7%, respectively; p<0.001, 20GI vs 30GI; p<0.01, IPC+30GI vs 30GI; p>0.05, 20GI vs IPC+30GI) but did not enhance postischemic functional recovery. The IPC+20GI hearts (3.5+/-0.6%) significantly decreased infarct size as compared with the 20GI hearts (p<0.05, IPC+20GI vs 20GI), and there was no significant difference between the IPC+20GI and the control hearts (p>0.05), but the IPC+20GI hearts did not enhance postischemic functional recovery. CONCLUSIONS: A 20 min ischemia may be the tolerable limitation time of prolonged ischemia after ischemic preconditioning in an isolated rabbit heart model.     

Sevoflurane and Isoflurane Protect the Reperfused Guinea Pig Heart by Reducing Postischemic Adhesion of Polymorphonuclear Neutrophils

Background: Polymorphonuclear neutrophils (PMNs) contribute to reperfusion injury. Because volatile anesthetics can reduce PMN adhesion in the reperfused, nonworking heart, the authors analyzed whether this action of volatile anesthetics affects cardiac performance after ischemia and reperfusion and further clarified the underlying mechanism.

Methods: Isolated guinea pig hearts perfused with crystalloid buffer and performing pressure-volume work were used. Hearts were subjected to 15 min global ischemia and 20 min reperfusion. In the intervention groups an intracoronary bolus of 3 x 106 PMNs was applied in the second min of reperfusion, either in the absence or presence of 0.5 or 1 minimum alveolar concentration sevoflurane or isoflurane. The number of sequestered PMNs was calculated from the difference between coronary input and output (coronary effluent) of PMNs. Performance of external heart work, determined pre- and postischemically, served as criterion for recovery of myocardial function. Additionally, the expression of the integrin CD11b on the cell surface of PMN was measured before and after coronary passage.

Results: Injection of PMN in the reperfusion phase, but not under nonischemic conditions, reduced recovery of external heart work significantly (from 55 +/- 7% to 19 +/- 11%). Addition of sevoflurane or isoflurane in concentrations of 0.5 and 1 minimum alveolar concentration to the perfusate reduced postischemic PMN adhesion from 36 +/- 8% to basal values (20 +/- 7%) and prevented decline of cardiac function. CD11b expression on PMNs increased significantly during postischemic coronary passage under control conditions. Again, both anesthetics in both concentrations inhibited that activation.     

Myocardial pyruvate, lactate, and orthophosphate contents under different postischemic conditions. A study in a paracorporeal rat heart model

The myocardial contents of pyruvate, lactate and orthophosphate after ischemia were investigated in a paracorporeal rat heart model under different conditions. The arterial blood was supplemented with phosphoenolpyruvate (PEP) and adenosine triphosphate early during reperfusion of excised hearts subjected to 15 min of complete global ischemia at 37 degrees C. The increase in myocardial pyruvate was significant after 4 min of reperfusion compared with the content in non-supplemented hearts subjected to the same ischemic trauma. Such dynamic changes were not observed for lactate and orthophosphate under corresponding conditions. The distinct increase in myocardial pyruvate content on supplementation with PEP and adenosine triphosphate was most probably due to an adenosine triphosphate-mediated PEP translocation into myocardial cells, with rapid metabolization of translocated PEP into adenosine triphosphate (in the presence of cellular adenosine diphosphate) and pyruvate. The pyruvate and lactate relationship varied, depending on the postischemic conditions. The postischemic myocardial orthophosphate content was stable, with only minor fluctuations. This possibility to supply the postischemic myocardium with substrate for immediate intracellular energy production is of clinical interest and merits further studies.     

Pinacidil pretreatment extends ischemia tolerance of neonatal rabbit hearts

OBJECTIVES: Activating ATP-sensitive potassium (K(ATP)) channels improves ischemia tolerance of adult rabbit hearts. We hypothesize that (a) endogenous activation of the K(ATP) channel accounts for better ischemia tolerance of neonatal hearts and (b) exogenous K(ATP) channel activation with pinacidil further improves the neonatal heart's tolerance to cardioplegic ischemia. METHODS: Study 1: Seven (control) neonatal rabbits received intraperitoneal saline, whereas five others (Glib) received 0.3 mg/kg glibenclamide 10 min before sacrifice. They were perfused on Langendorff with Krebs-Henseleit buffer (KHB). Baseline left ventricle (LV) performance and coronary flow (CF) were measured. After 20 min of 37 degrees C ischemia and 10 min of reperfusion, recovery was measured. Study 2: Ten (control) neonatal hearts underwent 90 min of normothermic ischemia with St. Thomas' cardioplegia (STCP) solution administered every 30 min. Ten others were pretreated with a 10-min infusion of 1 microM pinacidil in KHB and received 1 microM pinacidil-enriched STCP. Recovery of LV performance and CF were measured after 60 min of reperfusion. RESULTS: Study 1: Glib significantly reduced preischemia LV performance by 28%* compared to control hearts. Recovery of Glib-treated hearts was significantly less (67%*) than controls (81%*). Study 2: Pinacidil-treated hearts had significantly better recovery of LV performance (39%*) and CF (78%*) compared to 23 and 52%, respectively, in untreated controls (*P < 0.05 vs control hearts). CONCLUSIONS: Endogenous K(ATP) channel activation in neonatal hearts contributes to their better tolerance to ischemia. Exogenous K(ATP) channel activation by pinacidil pretreatment and cardioplegic enrichment significantly improved the neonatal rabbit heart's tolerance to cardioplegic ischemia. This may be an important addition to myocardial protection during pediatric cardiac surgery.     

Sevoflurane and isoflurane do not enhance the pre- and postischemic eicosanoid production in guinea pig hearts

Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 microM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2alpha. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%-60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5-8- and 2-4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane. IMPLICATIONS: In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.     

The protective effects of nifedipine in the isolated cat heart

The calcium channel blocking agent, nifedipine, was studied during global ischemia and reperfusion in isolated cat hearts perfused with Krebs-Henseleit solution. Nifedipine was added to the reservoir and 0.1 micrograms/ml perfusate/hr of nifedipine was infused for 150 min. After 120 min of ischemia (flow at 1% of control), the heart was reperfused with nifedipine-containing perfusate for 20 min and with nifedipine-free perfusate for an additional 25 min. In control hearts, nifedipine significantly reduced the percent free activity of the lysosomal protease cathepsin D (P less than 0.01). In ischemic hearts, nifedipine protected against the increased myocardial tissue edema (P less than 0.01), the increased percent free cathepsin D activity (P less than 0.02) and the postreperfusion increased creatine kinase activity (P less than 0.01). Thus, nifedipine showed membrane stabilizing and cytoprotective activities in myocardial cells, after postischemic reperfusion. These data suggest that calcium ions contribute to the lysosome labilization and cytoplasmic enzyme leakage observed in ischemia and reperfusion, and that calcium channel blockade may protect myocardial cellular integrity during both ischemia and reperfusion.