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.

scholarly journals Distinct Effects of Acute Pretreatment With Lipophilic and Hydrophilic Statins on Myocardial Stunning, Arrhythmias and Lethal Injury in the Rat Heart Subjected to Ischemia/Reperfusion

2011 ◽  
pp. 825-830 ◽  
Author(s):  
S. ČARNICKÁ ◽  
A. ADAMEOVÁ ◽  
M. NEMČEKOVÁ ◽  
J. MATEJÍKOVÁ ◽  
D. PANCZA ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Myocardial Stunning ◽  
Water Solubility ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Cells ◽  
Risk Area ◽  
Cardioprotective Effects ◽  
Developed Pressure

Although both lipophilic and more hydrophilic statins share the same pathway of the inhibition of HMG-CoA reductase, their pleiotropic cardioprotective effects associated with the ability to cross cellular membranes, including membranes of heart cells, may differ. To test this hypothesis, isolated rat hearts were Langendorff-perfused either with simvastatin (S, 10 μmol/l) or pravastatin (P, 30 μmol/l), 15 min prior to ischemia. Control untreated hearts (C) were perfused with perfusion medium only. Postischemic contractile dysfunction, reperfusion-induced ventricular arrhythmias and infarct size were investigated after exposure of the hearts to 30-min global ischemia and 2-h reperfusion. Both lipophilic S and hydrophilic P reduced the severity of ventricular arrhythmias (arrhythmia score) from 4.3±0.2 in C to 3.0±0 and 2.7±0.2 in S and P, respectively, (both P<0.05), decreased the duration of ventricular tachycardia and suppressed ventricular fibrillation. Likewise, the extent of lethal injury (infarct size) determined by tetrazolium staining and expressed in percentage of risk area, was significantly lower in both treated groups, moreover, the effect of P was more pronounced (27±2 % and 10±2 % in S and P groups, respectively, vs. 42±1 % in C; P<0.05). In contrast, only S, but not P, was able to improve postischemic recovery of left ventricular developed pressure (LVDP; 48±12 % of preischemic values vs. 25±4 % in C and 21±7 % in P groups; P<0.05). Our results suggest that differences in water solubility of statins indicating a different ability to cross cardiac membranes may underlie their distinct cardioprotective effects on myocardial stunning and lethal injury induced by ischemia/reperfusion.

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.

Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts

1995 ◽  
Vol 269 (3) ◽  
pp. H1030-H1036 ◽  
Author(s):  
B. L. Hamman ◽  
J. A. Bittl ◽  
W. E. Jacobus ◽  
P. D. Allen ◽  
R. S. Spencer ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Dynamic Range ◽  
Acute Stress ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Stress Conditions ◽  
Contractile Reserve ◽  
Phosphoryl Transfer ◽  
Rat Hearts ◽  
Developed Pressure

To define the relation between phosphoryl transfer via creatine kinase (CK) and the ability of the intact beating heart to do work, we chemically inhibited CK activity and then measured cardiac performance under physiological and acute stress conditions. Isolated perfused rat hearts were exposed to iodoacetamide (IA) and subjected to one of three cardiac stresses: hypercalcemic (Ca2+ = 3 mM) buffer perfusion (n = 7), norepinephrine (2 mumol/min) infusion (n = 6), or hypoxic buffer perfusion (n = 5). IA decreased CK activity to near zero, measured in intact hearts by 31P magnetization transfer, and to 2% of control CK activity, measured in myocardial homogenates. The CK isoenzyme profile was unchanged, suggesting nonselective IA inhibition of all isoenzymes. Mitochondria isolated from IA-treated hearts had normal ADP:O ratios, state 3 respiratory rates, and unchanged acceptor and respiratory control ratios. Neither actomyosin adenosinetriphosphatase nor adenylate kinase activities were changed. After IA exposure, end-diastolic pressure, left ventricular developed pressure, and heart rate were unchanged for at least 30 min at physiological perfusion pressures, but large changes were observed during stress conditions. The increase in left ventricular developed pressure induced by hypercalcemic perfusion and by norepinephrine infusion decreased by 39 and 54%, respectively. During hypoxia, the rate of phosphocreatine depletion was decreased by 57%, left ventricular developed pressure declined, and end-diastolic pressure increased faster than in controls. These results show that inhibition of CK to < 2% of control activity by IA reduced contractile reserve by approximately 50%. We conclude that CK activity is essential for the expression of the full dynamic range of myocardial performance.

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.

Adenosine A3 agonist cardioprotection in isolated rat and rabbit hearts is blocked by the A1 antagonist DPCPX

2001 ◽  
Vol 281 (2) ◽  
pp. H847-H853 ◽  
Author(s):  
Eric L. Kilpatrick ◽  
Prakash Narayan ◽  
Robert M. Mentzer ◽  
Robert D. Lasley
Keyword(s):  
Infarct Size ◽  
Receptor Activation ◽  
Left Ventricular ◽  
Ischemic Myocardium ◽  
Beneficial Effects ◽  
Rat Hearts ◽  
Rabbit Myocardium ◽  
Independent Effects ◽  
Developed Pressure ◽  
Isolated Rat

Adenosine A3 agonists have been shown to protect ischemic rat and rabbit myocardium. However, these agonists have been reported to exert A3 independent effects, and no cardiac A3 receptor has yet been identified. We thus tested whether A3 agonist protection is due to A1receptor activation. Isolated rat and rabbit hearts were subjected to 25 and 45 min of global ischemia, respectively. Rat hearts pretreated with adenosine (100 μM), the A3 agonist 2-chloro- N 6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (Cl-IB-MECA, 50 nM), and vehicle recovered 73 ± 2%, 75 ± 4%, and 46 ± 4%, respectively, of preischemic left ventricular developed pressure (LVDP) after 30 min of reperfusion. The A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM) blocked the beneficial effects of Cl-IB-MECA (51 ± 5%) and adenosine (47 ± 6%). In rabbit hearts, the beneficial effects of the A3 agonist N 6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (50 nM) and the A1 agonist 2-chloro- N 6-cyclopentyladenosine (100 nM) on postischemic LVDP (75 ± 4 and 74 ± 5%, respectively) were blocked by DPCPX (34 ± 4 and 36 ± 3%, respectively). The reduction in infarct size with both agonists was also completely blocked by DPCPX. These results suggest that these A3 agonists protect ischemic myocardium via A1 receptor activation.

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.

Attenuation of postischemic reperfusion injury is related to prevention of [Ca2+]m overload in rat hearts

1996 ◽  
Vol 271 (5) ◽  
pp. H2145-H2153 ◽  
Author(s):  
M. Miyamae ◽  
S. A. Camacho ◽  
M. W. Weiner ◽  
V. M. Figueredo
Keyword(s):  
Reperfusion Injury ◽  
Calcium Concentration ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Ruthenium Red ◽  
Free Calcium ◽  
Postischemic Reperfusion ◽  
Rat Hearts ◽  
Free Calcium Concentration ◽  
Developed Pressure

Intracellular calcium overload has been implicated in postischemic reperfusion injury. In myocytes, mitochondrial free calcium concentration ([Ca2+]m), not cytosolic free calcium concentration ([Ca2+]c), overload is related to reoxygenation injury. We tested the hypothesis that [Ca2+]m, not [Ca2+]c, overload is an important mediator of reperfusion injury in whole hearts. [Ca2+]m and [Ca2+]c were assessed using indo 1 fluorescence in isolated rat hearts subjected to 45 min of ischemia and 20 min of reperfusion. Ruthenium red (RR), a selective inhibitor of mitochondrial calcium uptake at 0.025 microM, attenuated the increase of [Ca2+]m (4% RR vs. 57% control) over preischemic levels (230 +/- 10 nM) but did not affect the increase of systolic [Ca2+]c (990 +/- 100 nM RR vs. 1,010 +/- 130 nM control). This was associated with improved recovery of left ventricular developed pressure (61% RR vs. 37% control) and attenuation of the increase of diastolic pressure (34 mmHg RR vs. 47 mmHg control). Contractile recovery was related to the degree of [Ca2+]m overload in both control and RR hearts (r2 = 0.47, P = 0.001). This study is the first to demonstrate that [Ca2+]m, and not [Ca2+]c, overload is related to reperfusion injury in intact beating hearts.

Prevention and reversal of altered myocardial function in diabetic rats by insulin treatment

1983 ◽  
Vol 61 (5) ◽  
pp. 516-523 ◽  
Author(s):  
Arun G. Tahiliani ◽  
Rao V. S. V. Vadlamudi ◽  
John H. McNeill
Keyword(s):  
Insulin Treatment ◽  
Myocardial Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Myocardial Performance ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Heart Preparation ◽  
Developed Pressure

Isolated perfused hearts from diabetic rats exhibit a decreased responsiveness to increasing work loads. However, the precise time point at which functional alterations occur is not clearly established. Previous observations in our laboratory have suggested that the alterations in myocardial function are not apparent at 30 days whereas they are clearly seen 100 days after streptozotocin-induced diabetes. We studied the cardiac function of 6-week diabetic rats using the isolated perfused heart preparation. The 6-week time period was found to be sufficient to cause depression of myocardial function in these animals. We also studied the effect of insulin treatment on myocardial performance of diabetic rats. Insulin treatment was initiated 3 days and 6 weeks after injection of streptozotocin (STZ). The treatment was continued for 6 and 4 weeks in the respective groups. Hearts from 6-week diabetic animals exhibited a depressed left ventricular developed pressure (LVDP) and positive and negative dP/dt at higher filling pressures when compared with 6-week control animals. However, the depression was not seen in the 6-week insulin-treated diabetic animals. Ten-week diabetic rat hearts also showed a depression of LVDP and positive and negative dP/dt when compared with 10-week controls. The group of animals that had been diabetic for 6 weeks and then treated for 4 weeks with insulin exhibited a reversal of the depressed myocardial function. These results demonstrate that depression of myocardial performance, which is evident 6 weeks after diabetes is induced, can be prevented if insulin treatment is initiated as the disease is induced. Further, insulin treatment is capable of reversing the abnormalities after they have occurred.

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.

scholarly journals Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning

2009 ◽  
Vol 297 (4) ◽  
pp. H1429-H1435 ◽  
Author(s):  
Donald A. Vessey ◽  
Luyi Li ◽  
Norman Honbo ◽  
Joel S. Karliner
Keyword(s):  
Infarct Size ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Left Ventricular ◽  
Rat Hearts ◽  
Sphingosine 1 Phosphate ◽  
Adenosine Antagonist ◽  
Specific Antagonist ◽  
Reoxygenation Injury ◽  
Developed Pressure

Exogenous sphingosine 1-phosphate (S1P) is an effective cardioprotectant against ischemic injury. We have investigated the hypothesis that S1P is also an important endogenous cardioprotectant released during both ischemic preconditioning (IPC) and ischemic postconditioning (IPOST). IPC of ex vivo rat hearts was instituted by two cycles of 3 min ischemia-5 min reperfusion prior to 40 min of index ischemia and then 40 min of reperfusion. IPC resulted in 70% recovery of left ventricular developed pressure (LVDP) upon reperfusion and a small infarct size (10%). VPC23019 (VPC), a specific antagonist of S1P1 and 3 G protein-coupled receptors (GPCRs), when present during preconditioning blocked protection afforded by two cycles of IPC. VPC also blocked preconditioning of isolated rat cardiac myocytes subjected to hypoxia-reoxygenation injury. Increased release of S1P from myocytes in response to IPC was also demonstrated. These data indicate that S1P is released from myocytes in response to IPC and protects by binding to S1P GPCRs. In the ex vivo heart, if a third cycle of IPC was added to increase release of endogenous mediators, then the need for any individual mediator (e.g., S1P) was diminished and VPC had little effect. The adenosine antagonist 8-( p-sulfophenyl)-theophylline (8-SPT) likewise inhibited protection by two cycles but not three cycles of IPC, but VPC plus 8-SPT inhibited protection by three cycles of IPC. Similar to IPC, IPOST induced by four postindex ischemia cycles of 15 s reperfusion-15 s ischemia resulted in 66% recovery of LVDP and a 7% infarct size. When VPC was present during postconditioning and reperfusion, LVDP only recovered by 26% and the infarct size increased to 27%. Adding an additional cycle of IPOST reduced the inhibitory effect of VPC and 8-SPT individually, but not their combined effect. These studies reveal that S1P is an important mediator of both IPC and IPOST that is released along with adenosine during each cycle of IPC or IPOST.

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