AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium

1999 ◽  
Vol 277 (6) ◽  
pp. H2482-H2487 ◽  
Author(s):  
Karyn L. Butler ◽  
Alice H. Huang ◽  
Judith K. Gwathmey
Keyword(s):  
Ischemic Preconditioning ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Weight ◽  
Rat Myocardium ◽  
Sprague Dawley ◽  
Isolated Hearts ◽  
Sd Rats ◽  
Developed Pressure

The purpose of this study was to determine whether ischemic preconditioning protects contractile function in hypertrophied rat myocardium from ischemia-reperfusion (I/R) injury. Male salt-sensitive rats were fed a high-salt diet for 2 wk to induce myocardial hypertrophy. Nonhypertrophied hearts were obtained from age-matched Sprague-Dawley (SD) rats fed a regular diet. Heart weight-to-body weight ratios were higher in salt-sensitive rats than in SD rats (6.9 ± 0.2 vs. 4.7 ± 0.2 g/kg, P < 0.01). A second group of salt-sensitive and SD rats was administered losartan (10 mg ⋅ kg−1 ⋅ day−1), an AT1-receptor blocker, for 1 wk before the study. Isolated hearts were preconditioned with transient ischemia before global I/R. After I/R, preconditioned hypertrophied hearts exhibited greater recovery of left ventricular developed pressure compared with that of preconditioned normal hearts (73 ± 8 vs. 18 ± 8%, P < 0.01). Left ventricular developed pressure was further enhanced by losartan in both hypertrophied and normal myocardium (99 ± 5 vs. 73 ± 8%, P < 0.05 and 97 ± 15 vs. 18 ± 8%, P < 0.01). Hypertrophied rat myocardium can be protected from I/R-induced contractile dysfunction by ischemic preconditioning. Losartan improves the ischemic tolerance of normal and hypertrophied myocardium.

Glibenclamide improves postischemic recovery of myocardial contractile function in trained and sedentary rats

2001 ◽  
Vol 91 (4) ◽  
pp. 1545-1554 ◽  
Author(s):  
Korinne N. Jew ◽  
Russell L. Moore
Keyword(s):  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Diastolic Stiffness ◽  
Pressure Development ◽  
Increased Sensitivity ◽  
Developed Pressure

In this study, we sought to determine whether there was any evidence for the idea that cardiac ATP-sensitive K+ (KATP) channels play a role in the training-induced increase in the resistance of the heart to ischemia-reperfusion (I/R) injury. To do so, the effects of training and an KATP channel blocker, glibenclamide (Glib), on the recovery of left ventricular (LV) contractile function after 45 min of ischemia and 45 min of reperfusion were examined. Female Sprague-Dawley rats were sedentary (Sed; n = 18) or were trained (Tr; n = 17) for >20 wk by treadmill running, and the hearts from these animals used in a Langendorff-perfused isovolumic LV preparation to assess contractile function. A significant increase in the amount of 72-kDa class of heat shock protein was observed in hearts isolated from Tr rats. The I/R protocol elicited significant and substantial decrements in LV developed pressure (LVDP), minimum pressure (MP), rate of pressure development, and rate of pressure decline and elevations in myocardial Ca2+ content in both Sed and Tr hearts. In addition, I/R elicited a significant increase in LV diastolic stiffness in Sed, but not Tr, hearts. When administered in the perfusate, Glib (1 μM) elicited a normalization of all indexes of LV contractile function and reductions in myocardial Ca2+content in both Sed and Tr hearts. Training increased the functional sensitivity of the heart to Glib because LVDP and MP values normalized more quickly with Glib treatment in the Tr than the Sed group. The increased sensitivity of Tr hearts to Glib is a novel finding that may implicate a role for cardiac KATP channels in the training-induced protection of the heart from I/R injury.

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.

scholarly journals STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?

2011 ◽  
Vol 300 (2) ◽  
pp. H522-H526 ◽  
Author(s):  
Michael D. Goodman ◽  
Sheryl E. Koch ◽  
Muhammad R. Afzal ◽  
Karyn L. Butler
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Subtype Specificity ◽  
Developed Pressure ◽  
Perfused Hearts

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/d tmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/d tmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.

scholarly journals Overexpression of A3 adenosine receptors decreases heart rate, preserves energetics, and protects ischemic hearts

2002 ◽  
Vol 283 (4) ◽  
pp. H1562-H1568 ◽  
Author(s):  
Heather R. Cross ◽  
Elizabeth Murphy ◽  
Richard G. Black ◽  
John Auchampach ◽  
Charles Steenbergen
Keyword(s):  
Heart Rate ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Atp Depletion ◽  
Wild Type ◽  
Basal Heart Rate ◽  
Developed Pressure

To determine whether A3 adenosine receptor (A3AR) signaling modulates myocardial function, energetics, and cardioprotection, hearts from wild-type and A3AR-overexpressor mice were subjected to 20-min ischemia and 40-min reperfusion while 31P NMR spectra were acquired. Basal heart rate and left ventricular developed pressure (LVDP) were lower in A3AR-overexpressor hearts than wild-type hearts. Ischemic ATP depletion was delayed and postischemic recoveries of contractile function, ATP, and phosphocreatine were greater in A3AR-hearts. To determine the role of depressed heart rate and to confirm A3AR-specific signaling, hearts were paced at 480 beats/min with or without 60 nmol/l MRS-1220 (A3AR-specific inhibitor) and then subjected to ischemia-reperfusion. LVDP was similar in paced A3AR-overexpressor and paced wild-type hearts. Differences in ischemic ATP depletion and postischemic contractile and energetic dysfunction remained in paced A3AR-overexpressor hearts versus paced wild-type hearts but were abolished by MRS-1220. In summary, A3AR overexpression decreased basal heart rate and contractility, preserved ischemic ATP, and decreased postischemic dysfunction. Pacing abolished the decreased contractility but not the ATP preservation or cardioprotection. Therefore, A3AR overexpression results in cardioprotection via a specific A3AR effect, possibly involving preservation of ATP during ischemia.

Positive inotropic effect of ceramide in adult ventricular myocytes: mechanisms dissociated from its reduction in Ca2+ influx

2003 ◽  
Vol 285 (2) ◽  
pp. H735-H744 ◽  
Author(s):  
Shi J. Liu ◽  
Richard H. Kennedy
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Adult Rat ◽  
Isolated Hearts ◽  
Developed Pressure ◽  
Contraction And Relaxation ◽  
State Contraction ◽  
Relationship Of

Ceramide, a sphingolipid metabolite produced by activation of sphingomyelinase, has been previously shown to reduce L-type Ca2+ channel current ( ICa,L) in adult rat ventricular myocytes; however, its effect on contractile function is unknown. In this study, we investigated the effects of ceramide on excitation-contraction coupling in adult ventricular myocytes and on left ventricular (LV) function in isolated hearts. Surprisingly, in patch-clamped myocytes, ceramide increased contraction concomitant with reductions in ICa,L. In intact myocytes, ceramide increased cell shortening (CS) concurrently with enhancing maximum rates of shortening and relaxation and the duration of contraction. Ceramide also increased the amplitudes of postrest potentiated (PRP) contraction. In fura-PE3-loaded myocytes, ceramide increased systolic Ca2+ and the magnitude and maximum rates of the rising and declining phases of Ca2+ transients. Ceramide-elicited decreases in magnitudes of PRP relative to steady-state contraction and the Ca2+ transient suggest an increased fractional Ca2+ release from the sarcoplasmic reticulum (SR). However, ceramide slightly reduced the caffeine-induced Ca2+ transient and had no significant effect on the amplitude of the PRP-elicited Ca2+ transient. Additionally, the ceramide-induced upward shift in the relationship of contraction and the Ca2+ transient and increase in the Ca2+ responsiveness of CS suggest an increase in myofilament Ca2+ sensitivity. In isolated hearts, ceramide increased LV developed pressure and maximum rates of contraction and relaxation at balloon volumes of 30–50 μl. In summary, regardless of decreasing ICa,L, ceramide elicits distinct positive inotropic and lusitropic effects, resulting probably from enhanced SR Ca2+ release and uptake, and increased Ca2+ sensitivity of ventricular myocytes.

Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats

2010 ◽  
Vol 299 (2) ◽  
pp. H265-H274 ◽  
Author(s):  
Marek Jankowski ◽  
Donghao Wang ◽  
Bogdan Danalache ◽  
Marius Gangal ◽  
Jolanta Gutkowska
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Sd Rats ◽  
Ovx Rats ◽  
Endothelial Nitric Oxide

An increasing amount of evidence demonstrates the beneficial role of oxytocin (OT) in the cardiovascular system. Similar actions are attributed to genistein, an isoflavonic phytoestrogen. The treatment with genistein activates the OT system in the aorta of ovariectomized (OVX) Sprague-Dawley (SD) rats. The objective of this study was to determine the effects of low doses of genistein on the OT-induced effects in rat hypertension. The hypothesis tested was that treatment of OVX spontaneously hypertensive rats (SHRs) with genistein improves heart structure and heart work through a mechanism involving the specific OT receptor (OTR). OVX SHRs or SD rats were treated with genistein (in μg/g body wt sc, 10 days) in the presence or absence of an OT antagonist (OTA) [d(CH2)5, Tyr(Me)2, Orn8]-vasotocin or a nonspecific estrogen receptor antagonist (ICI-182780). Vehicle-treated OVX rats served as controls. RT-PCR and Western blot analysis demonstrated that left ventricular (LV) OTR, downregulated by ovariectomy, increased in response to genistein. In SHRs or SD rats, this effect was blocked by OTA or ICI-182780 administration. The OTR was mainly localized in microvessels expressing the CD31 marker and colocalized with endothelial nitric oxide synthase. In SHRs, the genistein-stimulated OTR increases were associated with improved fractional shortening, decreased blood pressure (12 mmHg), decreased heart weight-to-body weight ratio, decreased fibrosis, and lowered brain natriuretic peptide in the LV. The prominent finding of the study is the detrimental effect of OTA treatment on the LV of SHRs. OTA treatment of OVX SHRs resulted in a dramatic worsening of ejection fractions and an augmented fibrosis. In conclusion, these results demonstrate that cardiac OTRs are involved in the regulation of cardiac function of OVX SHRs. The decreases of OTRs may contribute to cardiac pathology following menopause.

Abstract 222: Inhibition Of Class I But Not Class IIb Lysine Deacetylases Is Responsible For Cardioprotection From Ischemia-Reperfusion.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sverre E Aune ◽  
Santhosh K Mani ◽  
Donald R Menick
Keyword(s):  
Contractile Function ◽  
Trichostatin A ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Specific Inhibition ◽  
Isolated Hearts ◽  
Class Iib

Background: While dual inhibition of class I/IIb KDACs protects the mammalian heart from ischemia-reperfusion (IR) injury, class-specific effects have not been examined. Hypothesis: We hypothesized that specific inhibition of class I KDACs would preserve left ventricular (LV) function following IR in isolated hearts. Methods: Male Sprague-Dawley rats (n=4 per group) were injected with vehicle, the class I KDAC inhibitor entinostat, the class IIb inhibitor tubastatin A, or the class I/IIb inhibitor trichostatin A (TSA). After 18 h, hearts were isolated and perfused in Langendorff mode. A saline-filled balloon was placed in the LV to monitor contractile function. Following IR (30/120 min), LV free wall tissue was assayed for activation of pro-survival proteins. Group results are reported vs vehicle as mean±SE. Results: There were no differences between groups in LV function before ischemia. At the end of reperfusion, rate pressure product (mm hg/min) was improved with entinostat (27392±3474, p<0.001) and TSA (22980±3226, p<0.05) vs vehicle (11,352±1977), as were +dP/dt max and -dP/dt max . Most notably, entinostat alone blunted the rise in end diastolic pressure (mm Hg) during reperfusion (18.6±1.4 vs. 45.3±4.1, p<0.001), and completely prevented diastolic contracture (mm Hg) in reperfusion for up to one hour (12.4±2.0 vs pre-ischemia=8.7±1.7, p=0.21). Contractile function was not significantly preserved in hearts treated with tubastatin A. Entinostat reduced phosphorylation at the eNOS inhibitory site, and increased phosphorylation at the eNOS activation site, and Src activation was dramatically reduced. TSA increased activation of Src, p38, and ERK 1/2, and increased phosphorylation of eNOS at both the activation (Ser1177) and inhibition site (Thr495). Tubastatin A reduced activation of p38, ERK 1/2, and eNOS, but not Src. Conclusions: Inhibition of class I KDACs was most effective at preserving contractile function following IR in isolated hearts, notably through prevention of LV contracture during reperfusion. Class I KDAC inhibition may preserve LV function by differentially modulating Src and eNOS activities. These results suggest that the protective effects of KDAC inhibitors in IR can be ascribed to specific inhibition of class I KDACs.

STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium

2006 ◽  
Vol 291 (2) ◽  
pp. H797-H803 ◽  
Author(s):  
Karyn L. Butler ◽  
Lynn C. Huffman ◽  
Sheryl E. Koch ◽  
Harvey S. Hahn ◽  
Judith K. Gwathmey
Keyword(s):  
Ischemic Preconditioning ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Posterior Wall Thickness ◽  
Hypertrophied Myocardium ◽  
Developed Pressure

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 ± 58 vs. 1,028 ± 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/d tmax; 4,648 ± 309 vs. 2,737 ± 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum −dP/d t (−dP/d tmin; −2,239 ± 205 vs. −1,215 ± 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/d tmax(4,648 ± 309 vs. 3,241 ± 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and −dP/d tmin(−2,239 ± 205 vs. −1,323 ± 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.

Probucol promotes endogenous antioxidant reserve and confers protection against reperfusion injuryThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 439-443 ◽  
Author(s):  
Dinender K. Singla ◽  
Kuljeet Kaur ◽  
Anita K. Sharma ◽  
Sanjiv Dhingra ◽  
Pawan K. Singal
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Sprague Dawley ◽  
Isolated Hearts ◽  
Sprague Dawley Rats ◽  
Endogenous Antioxidant ◽  
Antioxidant Reserve

The present study examines whether a subchronic probucol treatment of rats offers protection against ischemia–reperfusion (IR) injury in isolated perfused hearts. Sprague–Dawley rats were treated every second day per week with probucol (cumulative dose 120 mg/kg body mass, i.p.) for 4 weeks. In the probucol group, baseline myocardial antioxidant enzyme, glutathione peroxidase (GSHPx), activity was increased (p < 0.05), whereas superoxide dismutase (SOD) and catalase (CAT) activities were not changed. Baseline oxidative stress, as indicated by the myocardial lipid peroxidation, was less (p < 0.05) in the probucol group. Isolated hearts were subjected to 60 min global I and 20 min R. Recovery of the contractile function in globally ischemic hearts upon reperfusion was 36% in untreated group and 74% in the probucol group. After IR, GSHPx and CAT activities were significantly (p < 0.05) higher in the probucol group compared with the control group, whereas SOD did not change. Lipid peroxidation owing to IR was significantly less in the probocol group. These data suggest that probucol treatment improves endogenous antioxidant reserve and protects against increased oxidative stress following IR injury.

P2X7 receptor agonists pre- and postcondition the heart against ischemia-reperfusion injury by opening pannexin-1/P2X7 channels

2011 ◽  
Vol 301 (3) ◽  
pp. H881-H887 ◽  
Author(s):  
Donald A. Vessey ◽  
Luyi Li ◽  
Michael Kelley
Keyword(s):  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
P2y Receptors ◽  
Left Ventricular ◽  
Ischemic Postconditioning ◽  
Risk Area ◽  
Pannexin 1 ◽  
Developed Pressure

Protection of the heart from ischemia-reperfusion injury can be achieved by ischemic preconditioning and ischemic postconditioning. Previous studies revealed that a complex of pannexin-1 with the P2X7 receptor forms a channel during ischemic preconditioning and ischemic postconditioning that results in the release of endogenous cardioprotectants. ATP binds to P2X7 receptors, inducing the formation of a channel in association with pannexin-1. We hypothesized that this channel would provide a pathway for the release of these same cardioprotectants. Preconditioning-isolated perfused rat hearts with 0.4 μM ATP preceding 40 min of ischemia minimized infarct size upon subsequent reperfusion (5% of risk area) and resulted in >80% recovery of left ventricular developed pressure. Postconditioning with ATP after ischemia during reperfusion was also protective (6% infarct and 72% recovery of left ventricular developed pressure). Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X7 receptors (brilliant blue G and A438079) blocked ATP pre- and postconditioning, indicating that ATP protection was elicited via the opening of a pannexin-1/P2X7 channel. An antagonist of binding of the endogenous cardioprotectant sphingosine 1-phosphate to its G protein-coupled receptor diminished protection by ATP, which is also consistent with an ATP-dependent release of cardioprotectants. Suramin, an antagonist of binding of ATP (and ADP) to P2Y receptors, was without effect on ATP protection. Benzoyl benzoyl-ATP, a more specific P2X7 agonist, was also a potent pre- and postconditioning agent and sensitive to blockade by pannexin-1/P2X7 channel antagonists. The data point out for the first time the potential of P2X7 agonists as cardioprotectants.

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