Abstract 374: Targeted Deletion of A 2B Adenosine Receptors Attenuates the Protective Effects of Myocardial Postconditioning

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xinglin Tan ◽  
Stephen L Tilley ◽  
Thomas Krahn ◽  
Bunyen Teng ◽  
S. J Mustafa ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Troponin I ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Weight ◽  
Receptor Subtypes ◽  
Protective Effects ◽  
Targeted Deletion ◽  
Beneficial Effects

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (PostCon). To assess the hypothesis that A 2B adenosine receptor (A 2B AR) activation contributes to PostCon-induced protection, global ischemia-reperfusion was performed with and without PostCon or the selective A 2B agonist, BAY 60 – 6583 (BAY), in isolated wild-type (WT) and A 2B AR knockout (A 2B KO) mouse hearts. In WT hearts, PostCon improved post-ischemic recovery of left ventricular developed pressure (LVDP) to 63.3±1.6 % of pre-ischemic baseline vs. 49.9±1.6 % in non-PostCon controls (CTL), lowered end diastolic pressure (EDP) to 15.8±1.5 mmHg vs. 27.9±1.6 mmHg in CTL, and reduced coronary efflux of cardiac troponin I (cTnI) to 2507±359 ng/g heart weight vs. 4693±343 ng/g in CTL (n=12 both groups, p <0.05 each comparison). Treatment with BAY in the first two min of reperfusion mimicked beneficial effects of PostCon in WT hearts (LVDP: 64.7±2.0 % baseline, EDP: 16.2±2.0 mmHg, cTnI: 3311±366; n=13, not significant compared to respective PostCon values). Real-time PCR confirmed absence of A 2B AR in A 2B KO hearts and demonstrated no changes in expression of other adenosine receptor subtypes compared with WT hearts. In A 2B KO hearts, neither PostCon nor BAY improved recovery of LVDP (50.8±1.6 % baseline for CTL vs. 54.5±1.7 % with PostCon vs. 53.0±1.4 with BAY; n=6 each group), and neither affected EDP or release of cTnI. During reperfusion, both PostCon and BAY increased survival kinase signaling through Akt and ERK1/2 phosphorylation in WT but not A 2B KO hearts. In non-ischemic WT hearts, Akt and ERK1/2 phosphorylation was increased by both BAY treatment and application of the PostCon stimulus. These data demonstrate that the protective effects of PostCon are attenuated by targeted deletion of A 2B AR and are mimicked by selective A 2B AR activation, suggesting A 2B AR activation is an important trigger leading to PostCon-induced myocardial protection.

Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning

2007 ◽  
Vol 293 (4) ◽  
pp. H2523-H2529 ◽  
Author(s):  
R. Ray Morrison ◽  
Xing Lin Tan ◽  
Catherine Ledent ◽  
S. Jamal Mustafa ◽  
Polly A. Hofmann
Keyword(s):  
Functional Recovery ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Troponin I ◽  
Ischemia Reperfusion ◽  
Receptor Subtype ◽  
Protective Effects ◽  
Targeted Deletion ◽  
Beneficial Effects ◽  
A2a Adenosine Receptors

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (POC), yet it is unclear which adenosine receptor subtype is primarily responsible. To evaluate the role of A2A adenosine receptors in POC-induced protection, global ischemia-reperfusion was performed with and without POC in isolated wild-type (WT) and A2A adenosine receptor knockout (A2AKO) mouse hearts. Injury was measured in terms of postischemic functional recovery and release of cardiac troponin I (cTnI). Activation of protective signaling with POC was assessed by Akt and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. In WT hearts, POC improved recovery of postischemic developed pressure in early (81.6 ± 6.4% of preischemic baseline vs. 37.5 ± 5.6% for non-POC WT at 1 min) and late (62.2 ± 4.2% of baseline vs. 45.5 ± 5.3% for non-POC WT at 30 min) reperfusion, reduced cTnI release by 37%, and doubled the phosphorylation of both Akt and ERK1/2. These beneficial effects of POC were blocked by treatment with the selective A2A adenosine receptor antagonist ZM-241385 during reperfusion. Postischemic functional recovery, cTnI release, and phosphorylation of Akt and ERK1/2 were not different between non-POC WT and A2AKO hearts. In A2AKO hearts, POC did not improve functional recovery, reduce cTnI release, nor increase phosphorylation of Akt or ERK1/2. Thus the protective effects of POC are attenuated by both selective A2A receptor antagonism and targeted deletion of the gene encoding A2A adenosine receptors. These observations support the conclusion that endogenous activation of A2A adenosine receptors is an essential trigger leading to the protective effects of POC in isolated murine hearts.

Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes

2006 ◽  
Vol 291 (4) ◽  
pp. H1875-H1882 ◽  
Author(s):  
R. Ray Morrison ◽  
Bunyen Teng ◽  
Peter J. Oldenburg ◽  
Laxmansa C. Katwa ◽  
Jurgen B. Schnermann ◽  
...  
Keyword(s):  
Real Time ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Receptor Subtypes ◽  
Rt Pcr ◽  
Targeted Deletion ◽  
Developed Pressure

To examine ischemic tolerance in the absence of A1 adenosine receptors (A1ARs), isolated wild-type (WT) and A1AR knockout (A1KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A1AR deletion and/or ischemia-reperfusion. A1KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A1AR deletion. After 20 min of ischemia, CF was attenuated in A1KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A1KO hearts (54.4 ± 5.1 vs. WT 81.1 ± 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Postischemic efflux of LDH was greater in A1KO compared with WT hearts. Real-time RT-PCR demonstrated the absence of A1AR transcript in A1KO hearts, and the message for A2A, A2B, and A3 adenosine receptors was similar in uninstrumented A1KO and WT hearts. Ischemia-reperfusion increased A2B mRNA expression 2.5-fold in both WT and A1KO hearts without changing A1 or A3 expression. In WT hearts, ischemia transiently doubled A2A mRNA, which returned to preischemic level upon reperfusion, a pattern not observed in A1KO hearts. Together, these data affirm the cardioprotective role of A1ARs and suggest that induced expression of other adenosine receptor subtypes may participate in the response to ischemia-reperfusion in isolated murine hearts.

scholarly journals Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

2014 ◽  
Vol 222 (2) ◽  
pp. 289-299 ◽  
Author(s):  
Takuya Yoshino ◽  
Tomohisa Nagoshi ◽  
Ryuko Anzawa ◽  
Yusuke Kashiwagi ◽  
Keiichi Ito ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Wistar Rat ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Independent Manner ◽  
Beneficial Effects ◽  
Physiological Dose

Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia–reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10−9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia–reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemia–reperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia–reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides

2005 ◽  
Vol 83 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Marie-Josée Dumoulin ◽  
Albert Adam ◽  
John Burnett ◽  
Denise Heublein ◽  
Nobuharu Yamaguchi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Natriuretic Peptides ◽  
Ace Inhibitor ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cardioprotective Effect ◽  
Protective Effects ◽  
Hoe 140

The objective of the present study was to assess the cardioprotective effect of dual NEP–ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg·kg–1·d–1). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.Key words: ACE inhibitors, omapatrilat, bradykinin, natriuretic peptide, ischemia, reperfusion.

Effects of exercise training on contractile function in myocardial trabeculae after ischemia-reperfusion

2005 ◽  
Vol 99 (1) ◽  
pp. 230-236 ◽  
Author(s):  
Hyosook Hwang ◽  
Peter J. Reiser ◽  
George E. Billman
Keyword(s):  
Exercise Training ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Isometric Force ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Aerobic Exercise Training ◽  
Protective Effects ◽  
Shortening Velocity ◽  
Cross Sectional

Potential protective effects of aerobic exercise training on the myocardium, before an ischemic event, are not completely understood. The purpose of the study was to investigate the effects of exercise training on contractile function after ischemia-reperfusion (Langendorff preparation with 15-min global ischemia/30-min reperfusion). Trabeculae were isolated from the left ventricles of both sedentary control and 10- to 12-wk treadmill exercise-trained rats. The maximal normalized isometric force (force/cross-sectional area; Po/CSA) and shortening velocity ( Vo) in isolated, skinned ventricular trabeculae were measured using the slack test. Ischemia-reperfusion induced significant contractile dysfunction in hearts from both sedentary and trained animals; left ventricular developed pressure (LVDP) and maximal rates of pressure development and relaxation (±dP/d tmax) decreased, whereas end-diastolic pressure (EDP) increased. However, this dysfunction (as expressed as percent change from the last 5 min before ischemia) was attenuated in trained myocardium [LVDP: sedentary −60.8 ± 6.4% (32.0 ± 5.5 mmHg) vs. trained −15.6 ± 8.6% (64.9 ± 6.6 mmHg); +dP/d tmax: sedentary −54.1 ± 4.7% (1,058.7 ± 124.2 mmHg/s) vs. trained −16.7 ± 8.4% (1,931.9 ± 188.3 mmHg/s); −dP/d tmax: sedentary −44.4 ± 2.5% (−829.3 ± 52.0 mmHg/s) vs. trained −17.9 ± 7.2% (−1,341.3 ± 142.8 mmHg/s); EDP: sedentary 539.5 ± 147.6%; (41.3 ± 6.0 mmHg) vs. trained 71.6 ± 30.6%; 11.4 ± 1.2 mmHg]. There was an average 26% increase in Po/CSA in trained trabeculae compared with sedentary controls, and this increase was not affected by ischemia-reperfusion. Ischemia-reperfusion reduced V0 by 39% in both control and trained trabeculae. The relative amount of the β-isoform of myosin heavy chain (MHC-β) was twofold greater in trained trabeculae as well as in the ventricular free walls. Despite a possible increase in the economy in the trained heart, presumed from a greater amount of MHC-β, ischemia-reperfusion reduced Vo, to a similar extent in both control and trained animals. Nevertheless, the trained myocardium appears to have a greater maximum force-generating ability that may, at least partially, compensate for reduced contractile function induced by a brief period of ischemia.

scholarly journals Lack of the effect of superoxide dismutase and catalase on Na+,K+-ATPase activity in stunned rabbit hearts

2008 ◽  
pp. S61-S66
Author(s):  
P Kaplán ◽  
M Matejovičová ◽  
P Herijgers ◽  
W Flameng
Keyword(s):  
Superoxide Dismutase ◽  
Antioxidant Enzymes ◽  
Atpase Activity ◽  
Cardiac Dysfunction ◽  
Myocardial Stunning ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Significant Loss ◽  
Protective Effects

Reactive oxygen species (ROS) have been implicated in the mechanism of postischemic contractile dysfunction, known as myocardial stunning. In this study, we examined protective effects of antioxidant enzymes, superoxide dismutase (SOD) and catalase, against ischemia/reperfusion-induced cardiac dysfunction and inhibition of Na+,K+-ATPase activity. Isolated Langendorff-perfused rabbit hearts were subjected to 15 min of global normothermic ischemia followed by 10 min reperfusion. The hearts treated with SOD plus catalase did not show significant recovery of left ventricular (LV) end-diastolic pressure compared with untreated ischemic reperfused hearts. Treatment with antioxidants had no protective effects on developed LV pressure or its maximal positive and negative first derivatives (+/-LVdP/dt). Myocardial stunning was accompanied by significant loss in sarcolemmal Na+,K+-ATPase activity and thiol group content. Inhibition of enzyme activity and oxidation of SH groups were not prevented by antioxidant enzymes. These results suggest that administration of SOD and catalase in perfusate do not protect significantly against cardiac dysfunction in stunned rabbit myocardium.

Activation of NF-κB is a critical element in the antiapoptotic effect of anesthetic preconditioning

2009 ◽  
Vol 296 (5) ◽  
pp. H1296-H1304 ◽  
Author(s):  
Xiyuan Lu ◽  
Hong Liu ◽  
Lianguo Wang ◽  
Saul Schaefer
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Reversible Inhibitor ◽  
Critical Element ◽  
Protective Effects ◽  
Anesthetic Preconditioning

Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-κB during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-κB activation before I/R is unknown. Therefore, these experiments tested the hypothesis that APC-induced ROS results in activation of NF-κB before I/R, with consequent increased expression of antiapoptotic proteins such as Bcl-2 and decreased apoptosis. Experiments utilized an established perfused heart rat model of sevoflurane APC and I/R. The role of NF-κB was defined by a novel method of transient inhibition of the regulatory kinase IKK using the reversible inhibitor SC-514. In addition to functional measures of left ventricular developed and end-diastolic pressure, phosphorylation of IκBα and activation of NF-κB were measured along with cytosolic protein content of Bcl-2, release of cytochrome c, and degradation of caspase-3. APC resulted in ROS-dependent phosphorylation of IκBα and activation of NF-κB before I/R. APC also increased the expression of Bcl-2 before I/R. In addition to functional protection following I/R, APC resulted in lower release of cytochrome c and caspase-3 degradation. These protective effects of APC were abolished by transient inhibition of IκBα phosphorylation and NF-κB activation by SC-514 followed by washout. ROS-dependent activation of NF-κB by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-κB activation before I/R should protect hearts from I/R injury.

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.

scholarly journals Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection

2011 ◽  
Vol 301 (3) ◽  
pp. H1183-H1189 ◽  
Author(s):  
Enbo Zhan ◽  
Victoria J. McIntosh ◽  
Robert D. Lasley
Keyword(s):  
Receptor Agonist ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Beneficial Effects ◽  
A1 Receptor ◽  
Developed Pressure ◽  
Adenosine A2a

All four adenosine receptor subtypes have been shown to play a role in cardioprotection, and there is evidence that all four subtypes may be expressed in cardiomyocytes. There is also increasing evidence that optimal adenosine cardioprotection requires the activation of more than one receptor subtype. The purpose of this study was to determine whether adenosine A2A and/or A2B receptors modulate adenosine A1 receptor-mediated cardioprotection. Isolated perfused hearts of wild-type (WT), A2A knockout (KO), and A2BKO mice, perfused at constant pressure and constant heart rate, underwent 30 min of global ischemia and 60 min of reperfusion. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 200 nM) was administrated 10 min before ischemia and for the first 10 min of reperfusion. Treatment with CHA significantly improved postischemic left ventricular developed pressure (74 ± 4% vs. 44 ± 4% of preischemic left ventricular developed pressure at 60 min of reperfusion) and reduced infarct size (30 ± 2% with CHA vs. 52 ± 5% in control) in WT hearts, effects that were blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). Treatments with the A2A receptor agonist CGS-21680 (200 nM) and the A2B agonist BAY 60-6583 (200 nM) did not exert any beneficial effects. Deletion of adenosine A2A or A2B receptor subtypes did not alter ischemia-reperfusion injury, but CHA failed to exert a cardioprotective effect in hearts of mice from either KO group. These findings indicate that both adenosine A2A and A2B receptors are required for adenosine A1 receptor-mediated cardioprotection, implicating a role for interactions among receptor subtypes.

Mechanisms of ischemic preconditioning effects on Ca2+paradox-induced changes in heart

2000 ◽  
Vol 278 (3) ◽  
pp. H1008-H1015 ◽  
Author(s):  
Ken-Ichi Kawabata ◽  
Thomas Netticadan ◽  
Mitsuru Osada ◽  
Kohji Tamura ◽  
Naranjan S. Dhalla
Keyword(s):  
Protein Kinase ◽  
Ischemic Preconditioning ◽  
Diastolic Pressure ◽  
Contractile Activity ◽  
Left Ventricular ◽  
Protective Effects ◽  
Sr Protein ◽  
Beneficial Effects ◽  
Adenosine Receptor Antagonist ◽  
Cardiac Contractile

The effects of ischemic preconditioning (IP) on changes in cardiac performance and sarcoplasmic reticulum (SR) function due to Ca2+ paradox were investigated. Isolated perfused hearts were subjected to IP (three cycles of 3-min ischemia and 3-min reperfusion) followed by Ca2+-free perfusion and reperfusion (Ca2+paradox). Perfusion of hearts with Ca2+-free medium for 5 min followed by reperfusion with Ca2+-containing medium for 30 min resulted in a dramatic decrease in the left ventricular (LV) developed pressure and a marked increase in LV end-diastolic pressure. Alterations in cardiac contractile activity due to Ca2+paradox were associated with depressed SR Ca2+-uptake, Ca2+-pump ATPase, and Ca2+-release activities as well as decreased SR protein contents for Ca2+-pump and Ca2+ channels. All these changes due to Ca2+paradox were significantly prevented in hearts subjected to IP. The protective effects of IP on Ca2+ paradox changes in cardiac contractile activity as well as SR Ca2+-pump and Ca2+-release activities were lost when the hearts were treated with 8-( p-sulfophenyl)-theophylline, an adenosine receptor antagonist; KN-93, a specific Ca2+/calmodulin-dependent protein kinase II (CaMK II) inhibitor; or chelerythrine chloride, a protein kinase C (PKC) inhibitor. These results indicate that IP rendered cardioprotection by preventing a depression in SR function in Ca2+ paradox hearts. Furthermore, these beneficial effects of IP may partly be mediated by adenosine receptors, PKC, and CaMK II.

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