scholarly journals Mitochondria Isolated from Hearts Subjected to Ischemia/Reperfusion Benefit from Adenine Nucleotide Translocase 1 Overexpression

Membranes ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 836
Author(s):  
Andrea Dörner ◽  
Oleg Lynetskiy ◽  
Gerhild Euler ◽  
Ulf Landmesser ◽  
Klaus-Dieter Schlüter ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Diastolic Function ◽  
Mitochondrial Function ◽  
Diastolic Pressure ◽  
Adenine Nucleotide ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Adenine Nucleotide Translocase ◽  
Inner Mitochondrial Membrane ◽  
Rat Hearts

Reperfusion is the only feasible therapy following myocardial infarction, but reperfusion has been shown to damage mitochondrial function and disrupt energy production in the heart. Adenine nucleotide translocase 1 (ANT1) facilitates the transfer of ADP/ATP across the inner mitochondrial membrane; therefore, we tested whether ANT1 exerts protective effects on mitochondrial function during ischemia/reperfusion (I/R). The hearts of wild-type (WT) and transgenic ANT1-overexpressing (ANT1-TG) rats were exposed to I/R injury using the standard Langendorff technique, after which mitochondrial function, hemodynamic parameters, infarct size, and components of the contractile apparatus were determined. ANT1-TG hearts expressed higher ANT protein levels, with reduced levels of oxidative 4-hydroxynonenal ANT modifications following I/R. ANT1-TG mitochondria isolated from I/R hearts displayed stable calcium retention capacity (CRC) and improved membrane potential stability compared with WT mitochondria. Mitochondria isolated from ANT1-TG hearts experienced less restricted oxygen consumption than WT mitochondria after I/R. Left ventricular diastolic pressure (Pdia) decreased in ANT1-TG hearts compared with WT hearts following I/R. Preserved diastolic function was accompanied by a decrease in the phospho-lamban (PLB)/sarcoplasmic reticulum calcium ATPase (SERCA2a) ratio in ANT1-TG hearts compared with that in WT hearts. In addition, the phosphorylated (P)-PLB/PLB ratio increased in ANT1-TG hearts after I/R but not in WT hearts, which indicated more effective calcium uptake into the sarcoplasmic reticulum in ANT1-TG hearts. In conclusion, ANT1-TG rat hearts coped more efficiently with I/R than WT rat hearts, which was reflected by preserved mitochondrial energy balance, diastolic function, and calcium dynamics after reperfusion.

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

2007 ◽  
Vol 292 (4) ◽  
pp. H1986-H1994 ◽  
Author(s):  
Zhanna Makazan ◽  
Harjot K. Saini ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Left Ventricular ◽  
Cardiac Performance ◽  
Developed Pressure

To study the mechanisms of mitochondrial dysfunction due to ischemia-reperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [ N-acetyl-l-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H2O2) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R.

scholarly journals Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

2017 ◽  
Vol 41 (3) ◽  
pp. 999-1010 ◽  
Author(s):  
Shasha Zhu ◽  
Tongda Xu ◽  
Yuanyuan Luo ◽  
Yingying Zhang ◽  
Haochen Xuan ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Diastolic Function ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Regulatory Function ◽  
Protective Mechanism ◽  
P38 Mapk Pathway ◽  
Rat Hearts ◽  
R Process

Background/Aims: A major challenge for current therapeutic strategies against ischemia/reperfusion (I/R) is the lack of effective drugs. Considering luteolin enhances the activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) to improve the systolic/diastolic function of rat hearts and cardiomyocytes during the I/R process, we studied the regulatory function of the p38 MAPK pathway in this protective mechanism. Methods: Isolated cardiomyocytes and perfused hearts were separately divided into five groups and used to investigate I/R. The phosphorylation of p38 and phospholamban (p-PLB), the levels and activity of SERCA2a and the levels of proteins related to apoptosis were measured. Apoptotic cells were assessed using the TUNEL assay. Single-cell shortening, Ca2+ transients, and the decay of the mitochondrial membrane potential (Δψm) were detected. Results: The p38 MAPK pathway was activated during the I/R process, and inhibiting it with SB203580 promoted p-PLB, which enhanced the activity of SERCA2a and relieved the calcium overload to promote the recovery of the Δψm and reduce cardiomyocyte apoptosis in I/R. Luteolin also suppressed the activation of the p38 MAPK pathway and showed cardioprotective effects during I/R injury. Conclusions: We conclude that luteolin enhances SERCA2a activity to improve systolic/diastolic function during I/R in rat hearts and cardiomyocytes by attenuating the inhibitive effects of the p38 pathway on p-PLB.

Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts

2005 ◽  
Vol 99 (3) ◽  
pp. 999-1005 ◽  
Author(s):  
Satoshi Takeda ◽  
Seibu Mochizuki ◽  
Harjot K. Saini ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Superoxide Dismutase ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Function ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Sr Protein ◽  
Release Channel ◽  
Beneficial Effects ◽  
Rat Hearts

To study the cardioprotective effects of vanadate on ischemia-reperfusion (I/R) injury, isolated rat hearts perfused at constant flow were subjected to global ischemia for 30 min followed by reperfusion for 30 min. In this experimental model, I/R markedly decreased ventricular developed pressure and increased end-diastolic pressure. Pretreatment of hearts with 4 μM vanadate attenuated I/R-induced cardiac dysfunction. The reduction in sarcoplasmic reticulum (SR) Ca2+ uptake and Ca2+ release, as well as SR protein contents for Ca2+-pump ATPase and Ca2+-release channel, was also prevented by vanadate. Pretreatment of hearts with an antioxidant mixture containing superoxide dismutase + catalase exerted effects similar to those of vanadate in I/R hearts. Postischemic treatment of hearts with vanadate or superoxide dismutase + catalase also had beneficial effects on I/R-induced changes in cardiac performance and SR function. Alterations in cardiac function and SR Ca2+ transport due to an oxyradical-generating system (xanthine + xanthine oxidase) or an oxidant (H2O2) were attenuated by treatment with vanadate. These results suggest that vanadate may exert beneficial effects on cardiac performance and SR function in I/R hearts because of its antioxidant action.

scholarly journals P1: CHOLINERGIC RECEPTOR FUNCTION IN CARDIAC ISCHEMIC PRECONDITIONING

2016 ◽  
Vol 64 (3) ◽  
pp. 817.2-817
Author(s):  
CW Mullan ◽  
SA Mavropolous ◽  
K Ojamaa
Keyword(s):  
Ischemic Preconditioning ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Structural Complexity ◽  
Cholinergic Receptor ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Inner Mitochondrial Membrane ◽  
Cardiac Contractile Function

Purpose of StudyCardiac acetylcholine (ACh) signaling is protective, but the role of ACh in ischemic preconditioning (IPC) remains largely unknown. We studied the effect of selective alpha-7 nicotinic ACh receptor (a7nAChR) antagonism by methyllycaconitine (MLA) on the functional benefits of IPC and the effects of this on mitochondrial complexity and inner mitochondrial membrane potential (ψM).Methods UsedMale Sprague Dawley rats (n=17, 322±17 g) were heparinized and anesthetized with 80 mg/kg pentobarbital IP, and their hearts excised and perfused at constant pressure with a non-circulating Langendorff apparatus. Left ventricular (LV) pressure (LVDP) and heart rate (HR) were continually measured with a fluid filled latex balloon attached to a pressure transducer. Treatment groups were: ischemia-reperfusion (IR)(n=6): 20 min. perfusion, 30 min. of global ischemia, 45 min. of reperfusion; IPC (n=5): 10 min. perfusion, 3 min. ischemia with 2 min. reperfusion repeated 3 times prior to IR protocol, IPC+MLA (n=6): 6 min. perfusion, 4 min. of infusion of MLA at 233 nM, IPC with MLA during reperfusion periods, then IR. Mitochondria were isolated from the LV free wall, stained for ψM and for size, and examined by Flow Cytometry with a BD LSRFortessa. Controls (C) (n=4) were freshly excised hearts from similar animals with identical anesthesia.Summary of ResultsIPC increased LV work product (LVDP times HR) as a percent of pre-ischemia (%P) during reperfusion compared to IR control, and this effect was attenuated by MLA pretreatment (IR=24.1±4.5%P, IPC=49.8±2.8%P, IPC+MLA=33.8±3.5%P, p<0.01). IPC reduced end diastolic pressure from IR levels, and this was partially prevented by MLA treatment (IR=78.8±7.7 mm Hg, IPC=18.8±6.6 mm Hg, IPC+MLA=46.3±8.6 mm Hg, p<0.05). IPC maintained mitochondrial structural complexity compared to IR (C=65±6% of total mitochondria, IPC=61±5%, IR=32±4%, p<0.01). MLA reduced the effect of IPC on ψM in intact mitochondria to IR levels (IR=67±10% of intact population, IPC=88±3%, IPC+MLA=71±4%, p<0.01).ConclusionsSignaling through the a7nAChR is necessary for the effect of IPC on maintaining ψM and cardiac contractile function after IR injury.

Effect of preconditioning on ryanodine-sensitive Ca2+ release from sarcoplasmic reticulum of rat heart

1996 ◽  
Vol 271 (3) ◽  
pp. H876-H881 ◽  
Author(s):  
M. Tani ◽  
Y. Asakura ◽  
H. Hasegawa ◽  
K. Shinmura ◽  
Y. Ebihara ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Function ◽  
Rat Heart ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Ventricular Tachyarrhythmias ◽  
Beneficial Effects ◽  
Rat Hearts ◽  
Developed Pressure ◽  
Isolated Rat

The effect of varying the number of preconditioning (PC) episodes on the recovery of cardiac function and on the function of the sarcoplasmic reticulum (SR) was investigated to determine the correlation between the effect of PC and SR function. Isolated rat hearts were subjected to zero to three 5-min episodes of global ischemia with intermittent perfusion (PC0-PC3) followed by 25 min of ischemia (I) and 30 min of reperfusion. The left ventricular (LV) pressure and SR 45Ca2+ uptake in the absence or presence of ryanodine were then measured. The increase in LV end-diastolic pressure and the incidence and duration of ventricular tachyarrhythmias during reperfusion decreased. The recovery of LV developed pressure, LV dP/dtmax and dP/dtmin, increased as the number of episodes of PC increased. The rates of SR 45Ca2+ uptake after PC and after reperfusion were lower in PC3 than in PC0. Conversely, the rate of 45Ca2+ uptake after I did not differ between PC0 and PC3. The ryanodine-sensitive Ca2+ release increased after I, and additional increases were observed during reperfusion in PC0, whereas the release after I and reperfusion decreased progressively in PC3. These observations show that the beneficial effects of PC are associated with a decrease in ryanodine-sensitive SR Ca2+ release.

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.

scholarly journals Protective Effects of Flavonoid Pomiferin on Heart Ischemia-Reperfusion

2007 ◽  
Vol 76 (3) ◽  
pp. 363-370
Author(s):  
J. Nečas ◽  
L. Bartošíková ◽  
T. Florian ◽  
J. Klusáková ◽  
V. Suchý ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Diastolic Pressure ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Lipid Peroxidation Product ◽  
Total Antioxidant Activity ◽  
Protective Effects ◽  
Rat Hearts ◽  
Total Antioxidant

The objective of the present 15-day study was to evaluate the cardioprotective potential of flavonoid pomiferin isolated from the infructences of Maclura pomifera, Moraceae, against ischemia-reperfusion induced injury in rat hearts as a model of antioxidant-based composite therapy. Studies were performed with isolated, modifi ed Langendorff-perfused rat hearts and ischemia of heart was initiated by stopping the coronary flow for 30 min, followed by 60 min of reperfusion (14 ml min-1). Wistar rats were divided into three groups. The treated group received pomiferin (5 mg/kg/day in 0.5% Avicel); the placebo group received only 0.5% Avicel; the intact group was left without any applications. Biochemical indicators of oxidative damage, lipid peroxidation product malondialdehyde, antioxidant enzymes (superoxide dismutase, glutathione peroxidase, total antioxidant activity in serum and myocardium has been evaluated. We also examined the effect of pomiferin on cardiac function (left ventricular end-diastolic pressure, left ventricular pressure, peak positive +dP/dt (rate of pressure development) after ischemia and reperfusion. Our results demonstrate that pomiferin attenuates the myocardial dysfunction provoked by ischemiareperfusion. This was confirmed by the increase in both the antioxidant enzyme values and the total antioxidant activity. The cardio-protection provided by pomiferin treatment results from the suppression of oxidative stress and correlates with the improved ventricular function.

Attenuation of ischemia–reperfusion-induced alterations in intracellular Ca2+ in cardiomyocytes from hearts treated with N-acetylcysteine and N-mercaptopropionylglycineThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

2009 ◽  
Vol 87 (12) ◽  
pp. 1110-1119 ◽  
Author(s):  
Harjot K. Saini-Chohan ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Redox Status ◽  
Left Ventricular ◽  
Cardiovascular Research ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Developed Pressure ◽  
Selection Of

This study was undertaken to test whether Ca2+-handling abnormalities in cardiomyocytes after ischemia–reperfusion (I/R) are prevented by antioxidants such as N-acetyl l-cysteine (NAC), which is known to reduce oxidative stress by increasing the glutathione redox status, and N-(2-mercaptopropionyl)-glycine (MPG), which scavenges both peroxynitrite and hydroxyl radicals. For this purpose, isolated rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion, and cardiomyocytes were prepared to monitor changes in the intracellular concentration of free Ca2+ ([Ca2+]i). Marked depression in the left ventricular developed pressure and elevation in the left ventricular end-diastolic pressure in I/R hearts were attenuated by treatment with NAC or MPG. Cardiomyocytes obtained from I/R hearts showed an increase in the basal level of [Ca2+]i as well as augmentation of the low Na+-induced increase in [Ca2+]i, with no change in the KCl-induced increase in [Ca2+]i. These I/R-induced alterations in Ca2+ handling by cardiomyocytes were attenuated by treatment of hearts with NAC or MPG. Furthermore, reduction in the isoproterenol-, ATP-, ouabain-, and caffeine-induced increases in [Ca2+]i in cardiomyocytes from I/R hearts were limited by treatment with NAC or MPG. The increases in the basal [Ca2+]i, unlike the KCl-induced increase in [Ca2+]i, were fully or partially prevented by both NAC and MPG upon exposing cardiomyocytes to hypoxia–reoxygenation, H2O2, or a mixture of xanthine and xanthine oxidase. These results suggest that improvement in cardiac function of I/R hearts treated with NAC or MPG was associated with attenuation of changes in Ca2+ handling by cardiomyocytes, and the results support the view that oxidative stress due to oxyradical generation and peroxynitrite formation plays an important role in the development of intracellular Ca2+ overload in cardiomyocytes as a consequence of I/R injury.

Abstract P237: Is Ischemia/Reperfusion an Efficient Method for Producing Heart Failure in Rats?

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ana Carolina M Omoto ◽  
Fábio N Gava ◽  
Mauro de Oliveira ◽  
Carlos A Silva ◽  
Rubens Fazan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Mitral Annulus ◽  
Mortality Rates ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Myocardium infarction (MI) elicited by coronary artery ligation (CAL) is commonly used to induce chronic heart failure (HF) in rats. However, CAL shows high mortality rates. Given that ischemia-reperfusion (IR) may cause the development of HF, this approach may be useful for obtaining a model of HF with low mortality rates. Therefore, it was compared the model of CAL vs. IR in rats, evaluating the mortality and cardiac morphological and functional aspects. The IR consisted of 30 minutes of cardiac ischemia. Wistar rats were assigned into three groups: CAL: n=18; IR: n=7; SHAM (fictitious IR): n=7. After four weeks of CAL, the subjects were evaluated by echocardiography and ventriculography as well. The statistical analysis consisted of ANOVA combined with Tukey’s posthoc test (p<0.05). There were no deaths in the IR and SHAM groups, whereas in the CAL group the mortality rate was 33.33% (6 out of 18). In the CAL group echocardiography showed increased left ventricular (LV) cavity during systole (8.3 ± 1mm) and diastole (10.5 ± 1mm); decreased LV free wall during systole (1.4 ± 0.5 mm); increased left atrium/aorta (2.3 ± 0.4) ratio. These changes were not significant in IR (4.8 ± 0.5mm, 7.6 ± 0.6mm, 2.6 ± 0.3 mm, 1.6 ± 0.2) and SHAM (4.6 ± 0.6 mm, 7.7 ± 0.8mm, 2.8 ± 0.4mm, 1.5 ± 0.2) groups. There was also the reduction in the ejection fraction in the CAL group (41 ± 12 %) when compared with IR (65 ± 9%) and SHAM (69 ± 7%) groups. The tissue Doppler analysis from the lateral mitral annulus showed reduction in E′ in CAL (-29 ± 8 mm/s) and IR (-31± 9 mm/s) groups when compared with the SHAM (-48 ± 11 mm/s) group. The ventriculography in the CAL group showed smaller maximum dP/dt (6519 ± 1062) and greater end-diastolic pressure (33 ± 8 mmHg) when compared with IR (8716 ± 756 mmHg/s; 9 ± 9 mmHg) and SHAM (7989 ± 1230 mmHg/s; 9 ± 7 mmHg) groups. The CAL group presented transmural infarct size of 40% of the left ventricular wall, measured under histopathological examination. In conclusion, IR for 30 minutes caused only small changes in LV diastolic function, assessed by tissue Doppler; however, the IR was not effective for promoting HF, as observed with CAL. Thus, it is possible that prolonged IR is necessary for promoting significant HF in rats.

Fasudil prevents KATP channel-induced improvement in postischemic functional recovery

2005 ◽  
Vol 288 (6) ◽  
pp. H3011-H3015 ◽  
Author(s):  
Kenya Nishizawa ◽  
Paul E. Wolkowicz ◽  
Tadashi Yamagishi ◽  
Ling-Ling Guo ◽  
Martin M. Pike
Keyword(s):  
Diastolic Pressure ◽  
Rho Kinase ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphate ◽  
Cellular Processes ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Rock Activity ◽  
Mechanical Recovery

Whereas activation of ATP-dependent potassium (KATP) channels greatly improves postischemic myocardial recovery, the final effector mechanism for KATP channel-induced cardioprotection remains elusive. RhoA is a GTPase that regulates a variety of cellular processes known to be involved with KATP channel cardioprotection. Our goal was to determine whether the activity of a key rhoA effector, rho kinase (ROCK), is required for KATP channel-induced cardioprotection. Four groups of perfused rat hearts were subjected to 36 min of zero-flow ischemia and 44 min of reperfusion with continuous measurements of mechanical function and 31P NMR high-energy phosphate data: 1) untreated, 2) pinacidil (10 μM) to activate KATP channels, 3) fasudil (15 μM) to inhibit ROCK, and 4) both fasudil and pinacidil. Pinacidil significantly improved postischemic mechanical recovery [39 ± 16 vs. 108 ± 4 mmHg left ventricular diastolic pressure (LVDP), untreated and pinacidil, respectively]. Fasudil did not affect reperfusion LVDP (41 ± 13 mmHg) but completely blocked the marked improvement in mechanical recovery that occurred with pinacidil treatment (54 ± 15 mmHg). Substantial attenuation of the postischemic energetic recovery was also observed. These data support the hypothesis that ROCK activity plays a role in KATP channel-induced cardioprotection.

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