Cardioprotective Effects of Propofol and Sevoflurane in Ischemic and Reperfused Rat Hearts 

1999 ◽  
Vol 91 (5) ◽  
pp. 1349-1349 ◽  
Author(s):  
Sanjiv Mathur ◽  
Parviz Farhangkhgoee ◽  
Morris Karmazyn
Keyword(s):  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphates ◽  
Constant Flow Rate ◽  
Rat Hearts ◽  
Reperfusion Period ◽  
Coronary Syndromes ◽  
Cardioprotective Effects ◽  
Developed Pressure

Background Sodium ion-hydrogen ion (Na(+)-H(+)) exchange inhibitors are effective cardioprotective agents. The N(+)-H(+) exchange inhibitor HOE 642 (cariporide) has undergone clinical trials in acute coronary syndromes, including bypass surgery. Propofol and sevoflurane are also cardioprotective via unknown mechanisms. The authors investigated the interaction between propofol and HOE 642 in the ischemic reperfused rat heart and studied the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels in the myocardial protection associated with propofol and sevoflurane. Methods Isolated rat hearts were perfused by the Langendorff method at a constant flow rate, and left ventricular function and coronary pressures were assessed using standard methods. Energy metabolites were also determined. To assess the role of K(ATP) channels, hearts were pretreated with the K(ATP) blocker glyburide (10 microM). Hearts were then exposed to either control buffer or buffer containing HOE 642 (5 microM), propofol (35 microM), sevoflurane (2.15 vol%), the K(ATP) opener pinacidil (1 microM), or the combination of propofol and HOE 642. Each heart was then subjected to 1 h of global ischemia followed by 1 h of reperfusion. Results Hearts treated with propofol, sevoflurane, pinacidil, or HOE 642 showed significantly higher recovery of left ventricular developed pressure and reduced end-diastolic pressures compared with controls. The combination of propofol and HOE 642 provided superior protection toward the end of the reperfusion period. Propofol, sevoflurane, and HOE 642 also attenuated the onset and magnitude of ischemic contracture and preserved high-energy phosphates (HEPs) compared with controls. Glyburide attenuated the cardioprotective effects of sevoflurane and abolished the protection observed with pinacidil. In contrast, glyburide had no effect on the cardioprotection associated with propofol treatment. Conclusion HOE 642, propofol, and sevoflurane provide cardioprotection via different mechanisms. These distinct mechanisms may allow for the additive and superior protection observed with the combination of these anesthetics and HOE 642.

Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia

1997 ◽  
Vol 272 (3) ◽  
pp. H1333-H1341 ◽  
Author(s):  
M. X. He ◽  
S. Wang ◽  
H. F. Downey
Keyword(s):  
Inorganic Phosphate ◽  
Contractile Force ◽  
Left Ventricular ◽  
Resonance Spectroscopy ◽  
Rat Hearts ◽  
Initial Control ◽  
Myocardial Contractile Force ◽  
Myocardial Contractile ◽  
Developed Pressure

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.

Inhibition of p38 MAPK α/β reduces ischemic injury and does not block protective effects of preconditioning

2001 ◽  
Vol 280 (2) ◽  
pp. H499-H508 ◽  
Author(s):  
Sharron Schneider ◽  
Weina Chen ◽  
Janet Hou ◽  
Charles Steenbergen ◽  
Elizabeth Murphy
Keyword(s):  
Treated Group ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride ◽  
Rat Hearts ◽  
Nuclear Magnetic Resonance Spectra ◽  
Mitogen Activated Protein ◽  
Reperfusion Period ◽  
Developed Pressure

We examined the effect of inhibition of p38 mitogen-activated protein kinase (MAPK) α/β during ischemia and preconditioning by using the inhibitor SB-202190. Isolated rat hearts were perfused with Krebs-Henseleit buffer, while left ventricular developed pressure (LVDP) and31P nuclear magnetic resonance spectra were acquired continuously. After 20 min of ischemia and 25 min of reperfusion, recovery of LVDP in untreated hearts was 32 ± 4%, whereas hearts treated with SB-202190 5 min before ischemia recovered 59 ± 7% of their pretreatment LVDP. Preconditioning improved functional recovery to 65 ± 5%, which was unaffected by SB-202190 treatment, added either throughout the preconditioning protocol (56 ± 5% recovery) or during the final reperfusion period of preconditioning (71 ± 11% recovery). Necrosis was assessed after 40 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride (TTC) staining and creatine kinase release. The untreated group had 54 ± 8% necrotic myocardium, whereas the SB-202190-treated group had 32 ± 7% and the preconditioned group had 21 ± 4% necrotic tissue by TTC staining.

Factors influencing myocardial response to metabolic acidosis in isolated rat hearts

1987 ◽  
Vol 253 (5) ◽  
pp. H1261-H1270 ◽  
Author(s):  
T. A. Watters ◽  
M. F. Wendland ◽  
W. W. Parmley ◽  
T. L. James ◽  
E. H. Botvinick ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Coronary Flow ◽  
Work Load ◽  
High Energy ◽  
High Energy Phosphates ◽  
Factors Influencing ◽  
Rat Hearts ◽  
Developed Pressure ◽  
High Work Load ◽  
High Work

We assessed the effects of metabolic acidosis in Langendorff rat hearts to identify factors influencing myocardial response to metabolic acidosis. Intracellular pH (pHi), beta-ATP, phosphocreatine, and inorganic phosphate (Pi) content were measured by 31P nuclear magnetic resonance spectroscopy along with simultaneous measurements of coronary flow and developed pressure during 30 min of perfusion at pH = 6.8, followed by 15 min of reequilibration at pH = 7.4. Under high work-load conditions, pHi, high-energy phosphates, coronary flow, and developed pressure were severely reduced during metabolic acidosis. Each of these hearts exhibited a progressive decline in developed pressure and stopped beating during reequilibration. Lowering work load prevented severe biochemical or mechanical deterioration, allowing complete recovery during reequilibration. In the presence of high work load, factors found to improve myocardial tolerance to metabolic acidosis included maintaining base-line or higher levels of coronary flow with vasodilators or substitution of pyruvate for glucose as the energy-producing substrate. Raising perfusate osmolality did not prevent severe decreases in coronary flow and developed pressure during acidosis, but did allow a dramatic recovery during reequilibration. Recovery of biochemical and mechanical performance after 30 min of metabolic acidosis was directly related to 1) ln[ATP]/[ADP]f[Pi] greater than or equal to 4.1, where [ADP]f is the concentration of free ADP; 2) pHi greater than 6.40; and 3) ATP level greater than or equal to 75% of control.

Sarpogrelate diminishes changes in energy stores and ultrastructure of the ischemic-reperfused rat heart

2001 ◽  
Vol 79 (9) ◽  
pp. 761-767 ◽  
Author(s):  
Rana M Temsah ◽  
Hideo Kumamoto ◽  
Nobuakira Takeda ◽  
Naranjan S Dhalla
Keyword(s):  
Serotonin Receptor ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
High Energy ◽  
Left Ventricular ◽  
Receptor Blockade ◽  
Vascular Abnormalities ◽  
Reperfusion Period ◽  
Developed Pressure

Although the involvement of serotonin in exacerbating vascular abnormalities in ischemic heart disease has been established, its role in mediating changes in cardiac function due to ischemia reperfusion (IR) is poorly understood. The aim of this study was to investigate the effect of a serotonin blocker, sarpogrelate (5-HT2A antagonist), in preventing cardiac injury due to IR. Isolated rat hearts were subjected to 30 min of global ischemia followed by 1 h of reperfusion. Sarpogrelate (50 nM-0.9 µM) was infused 10 min before ischemia as well as during the reperfusion period. The IR-induced changes in left ventricular developed pressure, left ventricular end diastolic pressure, rate of pressure development, and rate of pressure decay were attenuated (P < 0.05) with sarpogrelate treatment. Sarpogrelate also decreased the ultrastructural damage and improved the high energy phosphate level in the IR hearts (P < 0.05). This study provides evidence for the attenuation of IR-induced cardiac injury by 5-HT2A receptor blockade and supports the view that serotonin may contribute to the deleterious effects of IR in the heart.Key words: ischemia reperfusion, sarpogrelate, serotonin receptor blockade.

Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction

2007 ◽  
Vol 292 (6) ◽  
pp. H2921-H2926 ◽  
Author(s):  
Z. Zhu ◽  
P. A. Hofmann ◽  
J. K. Buolamwini
Keyword(s):  
Infarct Size ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Nucleoside Transport ◽  
Total Risk ◽  
Risk Area ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Cardioprotective Effects ◽  
Developed Pressure

We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 μM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 ± 4.0% ( P < 0.001) and 14.1 ± 2.0 mmHg ( P < 0.03) for compound 2-treated hearts and 79.2 ± 5.9% ( P < 0.002) and 7.5 ± 2.7 mmHg ( P < 0.01) for compound 4-treated hearts compared with 41.6 ± 5.2% and 42.5 ± 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg for hearts treated with 1 μM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 μM, with LVDP recovery and EDP increase of 76.0 ± 4.9% ( P < 0.003) and 14.1 ± 1.0 mmHg ( P < 0.03). At 1 μM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 ± 3.17 ( P < 0.001) for compound 4 and 37.5 ± 3.42 ( P < 0.01) for NBMPR vs. 51.08 ± 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR ( P < 0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.

Measurement of cytosolic free calcium in perfused rat heart using TF-BAPTA

1994 ◽  
Vol 266 (5) ◽  
pp. C1323-C1329 ◽  
Author(s):  
E. Murphy ◽  
C. Steenbergen ◽  
L. A. Levy ◽  
S. Gabel ◽  
R. E. London
Keyword(s):  
Rat Heart ◽  
High Energy ◽  
Left Ventricular ◽  
Free Calcium ◽  
High Energy Phosphates ◽  
Perfused Rat Heart ◽  
Fast Exchange ◽  
Exchange Kinetics ◽  
Developed Pressure ◽  
Dissociation Constant Kd

The feasibility and usefulness of loading 1,2-bis(2-amino-5,6-difluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (TF-BAPTA), a new high-dissociation constant (KD) (65 microM) Ca2+ indicator, into perfused rat heart is demonstrated. TF-BAPTA-loaded perfused rat heart showed less than a 10% reduction in left ventricular developed pressure. In addition, loading perfused rat heart with TF-BAPTA had no effect on cell high-energy phosphates measured by 31P-nuclear magnetic resonance (NMR). Cytosolic free Ca2+ (Ca2+i) can be monitored in TF-BAPTA-loaded perfused rat heart using 19F-NMR. TF-BAPTA has a Ca(2+)-insensitive resonance (6F) and a Ca(2+)-sensitive fluorine (5F) that responds to changes in Ca2+ binding with fast exchange kinetics at magnetic fields < or = 8.5 T. Thus the shift difference between the 5F and 6F resonances is a measure of Ca2+i. Given the high KD and the slight differences in intra- vs. extracellular fluorine shifts, TF-BAPTA is not well suited for measuring basal Ca2+i, but it is useful for measuring increases in Ca2+i above this level. For studies in which intracellular pH changes are significant, e.g., during ischemia, pH-dependent corrections must be made to obtain an accurate Ca2+i value. Given its fast exchange kinetics, TF-BAPTA is also useful for measurement of free Ca2+ in different compartments or cells with different Ca2+i. We show that the rise in Ca2+i is not uniform during prolonged global ischemia (60 min); several different Ca2+i values are present. Thus TF-BAPTA is a useful new indicator for measuring elevations in Ca2+i or compartmentation of Ca2+i.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of impaired energy metabolism during acidosis: role of oxidative metabolism

1992 ◽  
Vol 262 (6) ◽  
pp. H1818-H1822 ◽  
Author(s):  
G. Suleymanlar ◽  
H. Z. Zhou ◽  
M. McCormack ◽  
N. Elkins ◽  
R. Kucera ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Energy Metabolism ◽  
Respiratory Control ◽  
High Energy ◽  
Metabolic Effects ◽  
High Energy Phosphates ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Perfused Rat Hearts

Isolated perfused rat hearts were used to study the effects of metabolic acidosis on energy metabolism. Hearts perfused with different substrates (glucose, pyruvate, and succinate) were subjected to metabolic acidosis. With all substrates, there were comparable decrements in oxygen consumption (approximately 35%), cardiac function (decrease in first derivative of pressure of 65%), and similar changes in high-energy phosphates (approximately 150% increases in inorganic phosphate and 25% decreases in phosphocreatine concentrations) with metabolic acidosis. To further investigate the metabolic effects of acidosis, isolated cardiac mitochondria were exposed to different incubation media pH conditions and given simple metabolites (glutamate/malate, succinate, or pyruvate) or fatty acids (octanoate). Reduction of incubation media pH to 6.0 did not significantly affect either coupled respiration rate or the respiratory control ratio (RCR) with any substrate. These data suggest that metabolic acidosis induces decreases in energy production in the isolated perfused heart by inhibiting mitochondrial substrate utilization and not by impairing glycolysis. However, this impairment of mitochondrial function is not a direct effect of acidosis itself but appears to occur secondarily to some other effects of acidosis which are, as yet, incompletely understood.

Mitochondrial role in ischemia–reperfusion of rat hearts exposed to high-K+ cardioplegia and clonazepam: energetic and contractile consequences

2007 ◽  
Vol 85 (5) ◽  
pp. 483-496 ◽  
Author(s):  
A.E. Consolini ◽  
M.I. Ragone ◽  
P. Conforti ◽  
M.G. Volonté
Keyword(s):  
Heat Release ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphates ◽  
Rat Hearts ◽  
High K ◽  
Pressure Development ◽  
P Recovery

The role of the mitochondrial Na/Ca-exchanger (mNCX) in hearts exposed to ischemia–reperfusion (I/R) and pretreated with cardioplegia (CPG) was studied from a mechano-calorimetric approach. No-flow ischemia (ISCH) and reperfusion (REP) were developed in isolated rat hearts pretreated with 10 µmol/L clonazepam (CLZP), an inhibitor of the mNCX, and (or) a high K+ – low Ca2+ solution (CPG). Left ventricular end diastolic pressure (LVEDP), pressure development during beats (P), and the steady heat release (Ht) were continuously measured and muscle contents of ATP and PCr were analyzed at the end of REP. During REP, Ht increased more than P, reducing muscle economy (P/Ht) and the ATP content. CPG induced an increase in P recovery during REP (to 90% ± 10% of preISCH) with respect to nonpretreated hearts (control, C, to 64% ± 10%, p < 0.05). In contrast, CLZP reduced P recovery of CPG-hearts (50% ± 6.4%, p < 0.05) and increased LVEDP in C hearts. To evaluate effects on sarcoplasmic reticulum (SR) function, ischemic hearts were reperfused with 10 mmol/L caffeine –36 mmol/L Na (C – caff – low Na). It increased LVEDP, which afterwards slowly relaxed, whereas Ht increased (by about 6.5 mW/g). CLZP sped up the relaxation with higher ΔHt, C – caff – low Na produced higher contracture and lower Ht in perfused than in ischemic hearts. Values of ΔHt were compared with reported fluxes of Ca2+-transporters, suggesting that mitochondria may be in part responsible for the ΔHt during C – caff – low Na REP. Results suggest that ISCH–REP reduced the SR store for the recovery of contractility, but induced Ca2+ movement from the mitochondria to the SR stores. Also, mitochondria and SR are able to remove cytosolic Ca2+ during overloads (as under caffeine), through the mNCX and the uniporter. CPG increases Ca2+ cycling from mitochondria to the SR, which contributes to the higher recovery of P. In contrast, CLZP produces a deleterious effect on ISCH–REP associated with higher heat release and reduced resynthesis of high energy phosphates, which suggests the induction of mitochondrial Ca cycling and uncoupling.

Glycolysis is necessary to preserve myocardial Ca2+ homeostasis during beta-adrenergic stimulation

1993 ◽  
Vol 264 (3) ◽  
pp. H670-H678 ◽  
Author(s):  
K. Nakamura ◽  
H. Kusuoka ◽  
G. Ambrosio ◽  
L. C. Becker
Keyword(s):  
Diastolic Pressure ◽  
Superconducting Magnet ◽  
High Energy ◽  
Left Ventricular ◽  
19F Nmr ◽  
High Energy Phosphates ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Atp Production ◽  
Developed Pressure

Although ATP derived from glycolysis represents only a small fraction of total myocardial ATP production, metabolic compartmentation may result in preferential use of glycolytic ATP for certain membrane activities, including pumping of Ca2+ from the cytoplasm. We tested this hypothesis by looking for evidence of Ca2+ overload in normoxic perfused rabbit hearts given iodoacetate (IAA, 50 microM) to block glycolysis and isoproterenol (Iso, 0.05 microM) to stimulate Ca2+ entry. The hearts beat isovolumically and were perfused with 16 mM glucose and 5 or 10 mM pyruvate (to preserve oxidative metabolism) in a superconducting magnet for 31P-nuclear magnetic resonance (NMR) measurements of high energy phosphates or 19F-NMR measurements of intracellular free Ca2+ concentration ([Ca2+]i). IAA by itself had no effect on left ventricular (LV) developed pressure, end-diastolic pressure, pressure-rate product, or tissue high-energy phosphates. During exposure to Iso, mean LV end-diastolic pressure increased from 10.7 to 49.3 mmHg in hearts pretreated with IAA (n = 7) but did not change in control hearts (n = 7). During Iso, there were substantial reductions in developed pressure, ATP, and phosphocreatine in IAA-treated hearts but not in control hearts. After exposure to IAA and Iso, a doubling of diastolic [Ca2+]i was observed with 19F-NMR. In IAA-treated hearts, reduction of perfusate Ca2+ concentration from 2.5 to 0.6 mM during Iso exposure (n = 6) prevented the mechanical dysfunction and decrease in high-energy phosphates. These findings suggest that glycolysis is necessary to preserve myocardial Ca2+ homeostasis during beta-adrenergic stimulation.

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