scholarly journals Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate

1999 ◽  
Vol 276 (2) ◽  
pp. H496-H502 ◽  
Author(s):  
Paul M. Kerr ◽  
M.-Saadeh Suleiman ◽  
Andrew P. Halestrap
Keyword(s):  
Initial Phase ◽  
Citrate Synthase ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Left Ventricular ◽  
Rat Hearts ◽  
Lactate Output ◽  
Perfused Rat Hearts ◽  
Decreasing Ph ◽  
Developed Pressure

We have used mitochondrial entrapment of 2-deoxy-d-[3H]glucose (2-DG) to demonstrate that recovery of Langendorff-perfused rat hearts from ischemia is accompanied by reversal of the mitochondrial permeability transition (MPT). In hearts loaded with 2-DG before 40 min of ischemia and 25 min of reperfusion, 2-DG entrapment [expressed as 105 × (mitochondrial 2-[3H]DG dpm per unit citrate synthase)/(total heart 2-[3H]DG dpm/g wet wt)] increased from 11.1 ± 1.3 (no ischemia, n = 4) to 32.5 ± 1.9 ( n = 6; P < 0.001). In other experiments, 2-DG was loaded after 25 min of reperfusion to determine whether some mitochondria that had undergone the MPT during the initial phase of reperfusion subsequently “resealed” and thus no longer took up 2-DG. The reduction of 2-DG entrapment to 20.6 ± 2.4 units ( n = 5) confirmed that this was the case. Pyruvate (10 mM) in the perfusion medium increased recovery of left ventricular developed pressure from 57.2 ± 10.3 to 98.9 ± 10.8% ( n = 6; P < 0.05) and reduced entrapment of 2-DG loaded preischemically and postischemically to 23.5 ± 1.5 ( n = 4; P < 0.001) and 10.5 ± 0.5 ( n = 4; P < 0.01) units, respectively. The presence of pyruvate increased tissue lactate content at the end of ischemia and decreased the effluent pH during the initial phase of reperfusion concomitant with an increase in lactate output. We suggest that pyruvate may inhibit the MPT by decreasing pHi and scavenging free radicals, thus protecting hearts from reperfusion injury.

NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na(+)-H+ exchange

1993 ◽  
Vol 265 (6) ◽  
pp. H2017-H2026 ◽  
Author(s):  
M. M. Pike ◽  
C. S. Luo ◽  
M. D. Clark ◽  
K. A. Kirk ◽  
M. Kitakaze ◽  
...  
Keyword(s):  
Ph Regulation ◽  
Left Ventricular ◽  
Atp Depletion ◽  
Low Flow ◽  
Cellular Energy ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Ischemic Period ◽  
Developed Pressure ◽  
Zero Flow

Interleaved 23Na- and 31P-nuclear magnetic resonance (NMR) spectra were continuously collected on perfused rat hearts subjected to low-flow ischemia (30 min, 10% flow) or zero-flow ischemia (21 min) followed by reperfusion. During untreated low-flow and zero-flow ischemia, intracellular Na+ (Nai+) increased by 53 +/- 11 (+/- SE) and 78 +/- 8%, respectively, and remained elevated for zero-flow hearts. However, during both low- and zero-flow ischemia, Nai+ did not increase in hearts treated with the Na(+)-H+ exchange inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The pH decreases during ischemia were unchanged. EIPA treatment reduced ATP depletion during ischemia. During reperfusion from zero-flow ischemia, EIPA-treated hearts displayed more rapid and extensive recoveries of phosphocreatine and ATP. Recovery of left ventricular developed pressure was improved for zero-flow hearts treated with EIPA during the ischemic period exclusively (104 +/- 13%) compared with untreated hearts (36 +/- 21%). These data indicate that Na(+)-H+ exchange is an important mechanism for Nai+ accumulation, but not for pH regulation, during myocardial ischemia. Additionally, Nai+ homeostasis plays an important role in the postischemic recovery of cellular energy and ventricular function.

Effect of perfusate Ca2+ on the relation between metabolism and mechanical performance in the rat heart

1980 ◽  
Vol 58 (5) ◽  
pp. 570-573 ◽  
Author(s):  
T. Russell Snow ◽  
Gabor Rubanyi ◽  
Tunde Dora ◽  
Eörs Dora ◽  
Arisztid G. B. Kovach
Keyword(s):  
Respiratory Chain ◽  
Mechanical Performance ◽  
Left Ventricular ◽  
Perfused Heart ◽  
Exogenous Substrate ◽  
Rat Hearts ◽  
Nadh Fluorescence ◽  
Perfused Rat Hearts ◽  
Developed Pressure ◽  
Contractile Performance

Langendorf perfused rat hearts (n = 25) were used to study the effects of changes in perfusate Ca2+ concentration ([Ca2+p]) on the relation between metabolism and mechanical performance with either glucose or pyruvate as the exogenous substrate. Increased [Ca2+p] (from 1.3 to 3.9 mM) produced an increase (243 ± 38%) in left ventricular developed pressure regardless of the substrate. With glucose as the substrate, the NADH fluorescence intensity increased by 11.8 ± 1.2% (n = 17) relative to control indicating a more reduced state of the respiratory chain. Increasing [Ca2+p] in the pyruvate perfused heart produced the expected NADH oxidation (−6.2 ± 1.1%; n = 8). Hence the change in NADH fluorescence associated with increased [Ca2+p] is substrate dependent. The data show that, with glucose as the substrate but not with pyruvate, increases in [Ca2+p] increase the availability of reducing equivalents to the respiratory chain above the level necessary to compensate for the increased demand resulting from the greater contractile performance.

scholarly journals Hemidesmus indicusandHibiscus rosa-sinensisAffect Ischemia Reperfusion Injury in Isolated Rat Hearts

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Vinoth Kumar Megraj Khandelwal ◽  
R. Balaraman ◽  
Dezider Pancza ◽  
Táňa Ravingerová
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Moderate Increase ◽  
Dependent Manner ◽  
Hemidesmus Indicus ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Developed Pressure

Hemidesmus indicus(L.) R. Br. (HI) andHibiscus rosa-sinensisL. (HRS) are widely used traditional medicine. We investigated cardioprotective effects of these plants applied for 15 min at concentrations of 90, 180, and 360 μg/mL in Langendorff-perfused rat hearts prior to 25-min global ischemia/120-min reperfusion (I/R). Functional recovery (left ventricular developed pressure—LVDP, and rate of development of pressure), reperfusion arrhythmias, and infarct size (TTC staining) served as the endpoints. A transient increase in LVDP (32%–75%) occurred at all concentrations of HI, while coronary flow (CF) was significantly increased after HI 180 and 360. Only a moderate increase in LVDP (21% and 55%) and a tendency to increase CF was observed at HRS 180 and 360. HI and HRS at 180 and 360 significantly improved postischemic recovery of LVDP. Both the drugs dose-dependently reduced the numbers of ectopic beats and duration of ventricular tachycardia. The size of infarction was significantly decreased by HI 360, while HRS significantly reduced the infarct size at all concentrations in a dose-dependent manner. Thus, it can be concluded that HI might cause vasodilation, positive inotropic effect, and cardioprotection, while HRS might cause these effects at higher concentrations. However, further study is needed to elucidate the exact mechanism of their actions.

Catecholamines and preconditioning: studies of contraction and function in isolated rat hearts

1999 ◽  
Vol 277 (1) ◽  
pp. H136-H143 ◽  
Author(s):  
David J. Hearse ◽  
Fiona J. Sutherland
Keyword(s):  
Ischemic Preconditioning ◽  
Untreated Control ◽  
Vehicle Control ◽  
Left Ventricular ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Developed Pressure ◽  
And Function ◽  
Postischemic Recovery ◽  
Isolated Perfused Rat Hearts

The aims of this study were to determine whether 1) like ischemic preconditioning, transient exposure to norepinephrine before ischemia exacerbates contracture during ischemia and 2) protection afforded by norepinephrine is stereospecific (receptor mediated). Isolated perfused rat hearts were randomized into five groups ( n = 6/group): 1) ischemic preconditioning (3 min of ischemia + 3 min of reperfusion + 5 min of ischemia + 5 min of reperfusion), 2) untreated control, 3) vehicle control (ascorbic acid), 4) substitution of preconditioning ischemia by perfusion with d-norepinephrine, and 5) substitution of preconditioning ischemia by perfusion with l-norepinephrine. This was followed by 40 min of zero-flow ischemia and 50 min of reperfusion. Ischemic preconditioning and l-norepinephrine exacerbated contracture (time to 50% contracture = 9.2 ± 1.1 and 9.0 ± 1.1 vs. 13.3 ± 0.3, 12.4 ± 0.5, and 13.2 ± 0.4 min for untreated control, vehicle control, and d-norepinephrine, respectively, P < 0.05). Postischemic left ventricular developed pressure was poor in untreated control (23.0 ± 2.2%), vehicle control (26.9 ± 2.3%), and d-norepinephrine (19.8 ± 2.8%) groups but good in preconditioned (52.4 ± 5.1%) and l-norepinephrine (52.5 ± 1.1%) groups ( P < 0.05). Thus norepinephrine preconditioning, like ischemic preconditioning, causes a paradoxical exacerbation of contracture coupled with enhanced postischemic recovery; both effects are stereospecific.

Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury

2009 ◽  
Vol 296 (4) ◽  
pp. H1125-H1132 ◽  
Author(s):  
Masao Saotome ◽  
Hideki Katoh ◽  
Yasuhiro Yaguchi ◽  
Takamitsu Tanaka ◽  
Tsuyoshi Urushida ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Rat Hearts ◽  
Perfused Rat Hearts

Reactive oxygen species (ROS) production during ischemia-reperfusion (I/R) is thought to be a critical factor for myocardial injury. However, a small amount of ROS during the ischemic preconditioning (IPC) may provide a signal for cardioprotection. We have previously reported that the repetitive pretreatment of a small amount of ROS [hydrogen peroxide (H2O2), 2 μM] mimicked the IPC-induced cardioprotection in the Langendorff-perfused rat hearts. We further investigated the mechanisms of the ROS-induced cardioprotection against I/R injury and tested the hypothesis whether it could mediate the mitochondrial permeability transition pore (mPTP) opening. The Langendorff-perfused rat hearts were subjected to 35 min ischemia and 40 min reperfusion, and the pretreatment of H2O2 (2 μM) significantly improved the postischemic recoveries in left ventricular developed pressure, intracellular phosphocreatine, and ATP levels. A specific mPTP inhibitor cyclosporin A (CsA; 0.2 μM) canceled these H2O2-induced effects. In isolated permeabilized myocytes, H2O2 (1 μM) accelerated the calcein leakage from mitochondria in a CsA-sensitive manner, indicating the opening of mPTP by H2O2. However, H2O2 did not depolarize mitochondrial membrane potential (ΔΨm) even in the presence of oligomycin (F1/F0 ATPase inhibitor; 1 μM) and decreased mitochondrial Ca2+ concentration ([Ca2+]m) by accelerating the mitochondrial Ca2+ extrusion via an mPTP. We conclude that the transient mPTP opening could be involved in the H2O2-induced cardioprotection against reperfusion injury, and the reduction of [Ca2+]m without the change in ΔΨm might be a possible mechanism for the protection.

scholarly journals Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATPchannels

2008 ◽  
Vol 295 (3) ◽  
pp. H953-H961 ◽  
Author(s):  
Casey L. Quinlan ◽  
Alexandre D. T. Costa ◽  
Cinthia L. Costa ◽  
Sandrine V. Pierre ◽  
Pierre Dos Santos ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Signal Transmission ◽  
Permeability Transition ◽  
Cholesterol Depletion ◽  
Channel Opening ◽  
Rat Hearts ◽  
Plasma Membrane Receptor ◽  
Perfused Rat Hearts ◽  
Initial Support ◽  
Triton X

Perfusion of the heart with bradykinin triggers cellular signaling events that ultimately cause opening of mitochondrial ATP-sensitive K+(mitoKATP) channels, increased H2O2production, inhibition of the mitochondrial permeability transition (MPT), and cardioprotection. We hypothesized that the interaction of bradykinin with its receptor induces the assembly of a caveolar signaling platform (signalosome) that contains the enzymes of the signaling pathway and that migrates to mitochondria to induce mitoKATPchannel opening. We developed a novel method for isolating and purifying signalosomes from Langendorff-perfused rat hearts treated with bradykinin. Fractions containing the signalosomes were found to open mitoKATPchannels in mitochondria isolated from untreated hearts via the activation of mitochondrial PKC-ε. mitoKATPchannel opening required signalosome-dependent phosphorylation of an outer membrane protein. Immunodetection analysis revealed the presence of the bradykinin B2receptor only in the fraction isolated from bradykinin-treated hearts. Immunodetection and immunogold labeling of caveolin-3, as well as sensitivity to cholesterol depletion and resistance to Triton X-100, attested to the caveolar nature of the signalosomes. Ischemic preconditioning, ischemic postconditioning, and perfusion with ouabain also led to active signalosome fractions that opened mitoKATPchannels in mitochondria from untreated hearts. These results provide initial support for a novel mechanism for signal transmission from a plasma membrane receptor to mitoKATPchannels.

Adenosine A3-receptor stimulation attenuates postischemic dysfunction through KATP channels

1999 ◽  
Vol 277 (1) ◽  
pp. H228-H235 ◽  
Author(s):  
Vinod H. Thourani ◽  
Masanori Nakamura ◽  
Russell S. Ronson ◽  
James E. Jordan ◽  
Zhi-Qing Zhao ◽  
...  
Keyword(s):  
Katp Channels ◽  
Left Ventricular ◽  
Rate Of Change ◽  
Control Group ◽  
Receptor Stimulation ◽  
Rat Hearts ◽  
Positive Rate ◽  
Perfused Rat Hearts ◽  
Adenosine Agonists ◽  
Developed Pressure

We tested the hypothesis that selective adenosine A3-receptor stimulation reduces postischemic contractile dysfunction through activation of ATP-sensitive potassium (KATP) channels. Isolated, buffer-perfused rat hearts ( n = 8/group) were not drug pretreated (control) or were pretreated with adenosine (20 μM), 2-chloro- N 6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (Cl-IB-MECA; A3 agonist, 100 nM), Cl-IB-MECA + 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902; A1 antagonist, 5 μM), Cl-IB-MECA + glibenclamide (Glib; KATP-channel blocker, 0.3 μM), or Glib alone for 12 min before 30 min of global normothermic ischemia followed by 2 h of reperfusion. After 2 h of reperfusion, left ventricular developed pressure (LVDP, %baseline) in control hearts was depressed to 34 ± 2%. In hearts pretreated with Cl-IB-MECA, there was a statistically significant increase in LVDP (50 ± 6%), which was reversed with coadministration of Glib (37 ± 1%). Control hearts also showed similar decreases in left ventricular peak positive rate of change in pressure (dP/d t). Therefore, the A3 agonist significantly attenuated postischemic cardiodynamic injury compared with the control, which was reversed by Glib. Cumulative creatine kinase (CK in U/min) activity was most pronounced in the control group (10.4 ± 0.6) and was significantly decreased by Cl-IB-MECA (7.5 ± 0.4), which was reversed by coadministration of Glib (9.4 ± 0.2). Coronary flow was increased during adenosine infusion (160% of baseline) but not during Cl-IB-MECA infusion. Effects of Cl-IB-MECA were not reversed by the specific A1 antagonist KW-3902. We conclude that cardioprotection afforded by A3-receptor stimulation may be mediated in part by KATP channels. Cl-IB-MECA may be an effective pretreatment agent that attenuates postischemic cardiodynamic dysfunction and CK release without the vasodilator liability of other adenosine agonists.

Thermodynamic limitation for Ca2+ handling contributes to decreased contractile reserve in rat hearts

1998 ◽  
Vol 275 (6) ◽  
pp. H2064-H2071 ◽  
Author(s):  
Rong Tian ◽  
Jessica M. Halow ◽  
Markus Meyer ◽  
Wolfgang H. Dillmann ◽  
Vincent M. Figueredo ◽  
...  
Keyword(s):  
Atp Hydrolysis ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Contractile Reserve ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Perfused Rat Hearts ◽  
Thermodynamic Driving Force ◽  
Developed Pressure ◽  
Isolated Perfused Rat Hearts

The free energy release from ATP hydrolysis (‖ΔG∼p‖) is decreased by inhibiting the creatine kinase (CK) reaction, which may limit the thermodynamic driving force for the sarcoplasmic reticulum (SR) Ca2+ pumps and thereby cause a decrease in contractile reserve. To determine whether a decrease in ‖ΔG∼p‖ results in decreased contractile reserve by impairing Ca2+ handling, we measured left ventricular pressure and cytosolic Ca2+concentration ([Ca2+]c; by indo 1 fluorescence) in isolated perfused rat hearts, with >95% inhibition of CK with 90 μmol iodoacetamide. Iodoacetamide did not directly alter SR Ca2+-ATPase activity, baseline left ventricular developed pressure, or baseline [Ca2+]c. When perfusate Ca2+ concentration was increased from 1.2 to 3.3 mM, LV developed pressure increased from 67 ± 6 to 119 ± 8 mmHg in control hearts ( P < 0.05) but did not significantly increase in CK-inhibited hearts. Similarly, the amplitude of the [Ca2+]ctransient increased from 548 ± 54 to 852 ± 140 nM in control hearts ( P < 0.05) but did not significantly increase in CK-inhibited hearts. We conclude that decreased ‖ΔG∼p‖ limits intracellular Ca2+ handling and thereby limits contractile reserve.

Effects of endotoxin on neutrophil-mediated I/R injury in isolated perfused rat hearts

2001 ◽  
Vol 280 (2) ◽  
pp. H802-H811 ◽  
Author(s):  
Brian P. Lipton ◽  
Abraham P. Bautista ◽  
Joseph B. Delcarpio ◽  
Kathleen H. McDonough
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Isolated Rat Heart ◽  
Polymorphonuclear Neutrophils ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Developed Pressure

With the use of a syngeneic model, we demonstrate that rat polymorphonuclear neutrophils (PMNs) exacerbate ischemia-reperfusion injury in the isolated rat heart. However, PMNs (19 × 106cells) from lipopolysaccharide (LPS)-treated rats (LPS-PMNs; 100 mg/kg administered 7 h before exsanguination) induce less reperfusion injury in the isolated heart. Average recovery of left ventricular developed pressure after 20 min of ischemia and 60 min of reperfusion was 51 ± 4% in hearts receiving PMNs from saline-treated control rats (saline-PMNs) versus 78 ± 2% in hearts receiving LPS-PMNs. Ischemic hearts reperfused with LPS-PMNs recovered to the same extent as did hearts reperfused with Krebs buffer only. LPS-PMNs and saline-PMNs showed no difference in basal or phorbol ester-induced superoxide production. Whereas twice the number of LPS-PMNs was positive for nitroblue tetrazolium, the percent positive for L-selectin, a receptor integral in PMN-adhesion to endothelium, was 50% less in LPS-PMNs than in controls. After reperfusion, three-fourths of the saline-PMNs remained within the hearts, whereas only one-fourth of LPS-PMNs were trapped. These data suggest that PMNs from LPS-treated rats do not exacerbate ischemia-reperfusion injury as do control PMNs, possibly, due to impaired PMN adhesion to endothelium as a result of decreased L-selectin receptors.

Effects of perfusion pressure on intracellular calcium, energetics, and function in perfused rat hearts

1993 ◽  
Vol 264 (1) ◽  
pp. H183-H189 ◽  
Author(s):  
S. Kojima ◽  
S. T. Wu ◽  
T. A. Watters ◽  
W. W. Parmley ◽  
J. Wikman-Coffelt
Keyword(s):  
Perfusion Pressure ◽  
Left Ventricular Pressure ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Left Ventricular Geometry ◽  
Fluorescence Ratio ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Developed Pressure ◽  
And Function

Effects of perfusion pressure in a range from 50 to 140 cmH2O on intracellular Ca2+ concentration ([Ca2+]i) were evaluated along with cardiac function, energy metabolism, and left ventricular geometry in a concentration of 2 or 4 mM of extracellular Ca2+ ([Ca2+]o) in isovolumic perfused rat hearts. [Ca2+]i was evaluated with a surface fluorometry technique in hearts loaded with indo-1/AM. The systolic and diastolic values and the amplitude (difference between systolic and diastolic values) of indo-1 fluorescence ratio (an index of [Ca2+]i) were linearly related to perfusion pressure. Changes in the fluorescence ratio were harmonious with rapid changes in left ventricular pressure and stabilized within 30-40 s after changes in perfusion pressure. Developed pressure and O2 consumption were closely, linearly correlated with the fluorescence ratio irrespective of [Ca2+]o. Left ventricular end-diastolic wall thickness, measured by 2-dimensional echocardiography, paralleled perfusion pressure and showed a good correlation with the fluorescence ratio. Diastolic myocardial adenosine 3',5'-cyclic monophosphate significantly decreased only at the lowest perfusion pressure. The ln[phosphocreatine]/[Pi] also changed with altered perfusion pressure. In conclusion, perfusion pressure modulates [Ca2+]i, which in turn regulates myocardial contraction and associated O2 utilization.

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