Nonanticoagulant heparin reduces myocyte Na+ and Ca2+ loading during simulated ischemia and decreases reperfusion injury

Heparin desulfated at the 2- O and 3- O positions (ODSH) decreases canine myocardial reperfusion injury. We hypothesized that this occurs from effects on ion channels rather than solely from anti-inflammatory activities, as previously proposed. We studied closed-chest pigs with balloon left anterior descending coronary artery occlusion (75-min) and reperfusion (3-h). ODSH effects on [Na+]i (Na Green) and [Ca2+]i (Fluo-3) were measured by flow cytometry in rabbit ventricular myocytes after 45-min of simulated ischemia [metabolic inhibition with 2 mM cyanide, 0 glucose, 37°C, pacing at 0.5 Hz; i.e., pacing-metabolic inhibition (PMI)]. Na+/Ca2+ exchange (NCX) activity and Na+ channel function were assessed by voltage clamping. ODSH (15 mg/kg) 5 min before reperfusion significantly decreased myocardial necrosis, but neutrophil influx into reperfused myocardium was not consistently reduced. ODSH (100 μg/ml) reduced [Na+]i and [Ca2+]i during PMI. The NCX inhibitor KB-R7943 (10 μM) or the late Na+ current ( INa-L) inhibitor ranolazine (10 μM) reduced [Ca2+]i during PMI and prevented effects of ODSH on Ca2+ loading. ODSH also reduced the increase in Na+ loading in paced myocytes caused by 10 nM sea anemone toxin II, a selective activator of INa-L. ODSH directly stimulated NCX and reduced INa-L. These results suggest that in the intact heart ODSH reduces Na+ influx during early reperfusion, when INa-L is activated by a burst of reactive oxygen production. This reduces Na+ overload and thus Ca2+ influx via NCX. Stimulation of Ca2+ extrusion via NCX later after reperfusion may also reduce myocyte Ca2+ loading and decrease infarct size.

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Abstract 13780: Effects of Op2113 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/reperfusion Model

Circulation ◽

10.1161/circ.142.suppl_3.13780 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Wangde Dai ◽

Bruno Le Grand ◽

Aurelie Boucard ◽

Juan Carreno ◽

lifu Zhao ◽

...

Keyword(s):

Coronary Artery ◽

Infarct Size ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Vehicle Group ◽

Tetrazolium Chloride ◽

Early Reperfusion ◽

Risk Zone ◽

No Reflow ◽

No Reflow Phenomenon

Background: Despite advances in early reperfusion therapy for acute ST elevation myocardial infarction (MI), mortality rates and prevention of heart failure after the MI are not optimal. There have been many attempts to further reduce the size of acute MI and to limit the no reflow phenomenon after reperfusion, with mixed results. One promising approach may be to target the mitochondria. The purpose of the present study was to determine whether OP2113 and its active principle ATT (Anethol-TriThione, named also 5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione; CAS 532-11-6 ), a pharmaceutical that has been shown to decrease mitochondrial reactive species production from complex I of the mitochondrial respiratory chain, could limit MI size and the no reflow phenomenon in a standardized rat model of 30 minutes of proximal coronary artery occlusion and reperfusion. Methods and Results: Anesthetized rats were exposed to MI and received OP2113 as an intravenous infusion starting either 5 minutes prior to coronary artery occlusion (preventive), or 5 minutes prior to reperfusion (curative), or received vehicle starting 5 minutes prior to coronary artery occlusion. Infusions continued until the end of the study (3 hours of reperfusion). MI size ( triphenyl tetrazolium chloride staining technique) , expressed as a percentage of the ischemic risk zone ( blue dye technique) was significantly lower in the OP2113 treated preventive group at 44.5 ± 2.9% versus 57.0 ± 3.6% ( p<0.05) in the vehicle group, with a nonsignificant trend toward a smaller infarct size in the curative group ( 50.8 ± 3.9%). Area of no reflow ( thioflavin S technique) as a percentage of the risk zone was significantly smaller in both the OP2113 treated preventive (28.8 ± 2.4%; p =0.026 vs vehicle) and curative groups ( 30.1 ± 2.3%; p=0.04 vs vehicle) compared to the vehicle group ( 38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes. Conclusions: These results suggest that OP2113 is a promising agent to reduce no-reflow as well as to reduce MI size, especially if it is on board early in the course of the MI. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia.

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Temporal relation between neutrophil accumulation and myocardial reperfusion injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.5.h1060 ◽

1988 ◽

Vol 255 (5) ◽

pp. H1060-H1068 ◽

Cited By ~ 6

Author(s):

E. F. Smith ◽

J. W. Egan ◽

P. J. Bugelski ◽

L. M. Hillegass ◽

D. E. Hill ◽

...

Keyword(s):

Coronary Artery ◽

Reperfusion Injury ◽

Time Course ◽

Myocardial Injury ◽

Inflammatory Cells ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Neutrophil Accumulation ◽

Cell Responses ◽

Significant Linear Correlation

Infiltration of polymorphonuclear leukocytes (PMN) is associated with the progression of myocardial infarction and reperfusion injury. However, little is known about the time course of cellular infiltration. To investigate this issue, rats were subjected to 30 min of coronary artery occlusion followed by reperfusion for less than or equal to 96 h. Myocardial injury was determined by measuring the depletion of myocardial creatine phosphokinase activity, and PMN infiltration was assessed by measuring myeloperoxidase (MPO) activity. MPO activity increased from 0.7 U/g tissue in non-operated animals, to a peak of 6.7 +/- 0.8 and 6.4 +/- 1.4 U/g at 6 and 24 h after coronary artery reperfusion, respectively. MPO activity decreased to 3.3 +/- 0.8 U/g at 48 h and 1.1 +/- 0.4 U/g at 96 h, suggesting diminished PMN accumulation. Histological examination confirmed the accumulation and resolution of PMN over the 96-h period. At 24 h, there was a significant linear correlation between infarct size and MPO activity, whereas at 96 h no relationship was found. These data indicate that PMN infiltration occurs early in response to reperfusion injury and persists for only 24 h after initiation of reperfusion. These findings suggest that attempts to moderate inflammatory cell responses to myocardial injury should be administered early after coronary artery reperfusion to limit the accumulation of potentially deleterious inflammatory cells.

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Use of changes in the epicardial QRS complex to assess interventions which modify the extent of myocardial necrosis following coronary artery occlusion.

Circulation ◽

10.1161/01.cir.54.4.591 ◽

1976 ◽

Vol 54 (4) ◽

pp. 591-598 ◽

Cited By ~ 108

Author(s):

L D Hillis ◽

J Askenazi ◽

E Braunwald ◽

P Radvany ◽

J E Muller ◽

...

Keyword(s):

Coronary Artery ◽

Myocardial Necrosis ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Qrs Complex

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Sites of action of adenosine in interorgan preconditioning of the heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01031.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. H29-H37 ◽

Cited By ~ 121

Author(s):

David A. Liem ◽

Pieter D. Verdouw ◽

Harald Ploeg ◽

Shahla Kazim ◽

Dirk J. Duncker

Keyword(s):

Adenosine Receptors ◽

Mesenteric Artery ◽

Intestinal Ischemia ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Early Reperfusion ◽

Afferent Nerves ◽

Small Intestinal ◽

Sites Of Action ◽

Mesenteric Artery Occlusion

The mechanism underlying interorgan preconditioning of the heart remains elusive, although a role for adenosine and activation of a neurogenic pathway has been postulated. We tested in rats the hypothesis that adenosine released by the remote ischemic organ stimulates local afferent nerves, which leads to activation of myocardial adenosine receptors. Preconditioning with a 15-min mesenteric artery occlusion (MAO15) reduced infarct size produced by a 60-min coronary artery occlusion (60-min CAO) from 68 ± 2% to 48 ± 4% ( P < 0.05). Pretreatment with the ganglion blocker hexamethonium or 8-( p-sulfophenyl)theophylline (8-SPT) abolished the protection by MAO15. Intramesenteric artery (but not intraportal vein) infusion of adenosine (10 μg/min) was as cardioprotective as MAO15, which was also abolished by hexamethonium. Whereas administration of hexamethonium at 5 min of reperfusion following MAO15 had no effect, 8-SPT at 5 min of reperfusion abolished the protection. Permanent reocclusion of the mesenteric artery before the 60-min CAO enhanced the cardioprotection by MAO15 (30 ± 5%), but all protection was abolished when 8-SPT was administered after reocclusion of the mesenteric artery. Together, these findings demonstrate the involvement of myocardial adenosine receptors. We therefore conclude that locally released adenosine during small intestinal ischemia stimulates afferent nerves in the mesenteric bed during early reperfusion, initiating a neurogenic pathway that leads to activation of myocardial adenosine receptors.

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Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1981.240.2.h156 ◽

1981 ◽

Vol 240 (2) ◽

pp. H156-H163 ◽

Cited By ~ 5

Author(s):

J. E. Skinner ◽

J. C. Reed

Keyword(s):

Ventricular Fibrillation ◽

Frontal Cortex ◽

Brain Stem ◽

Myocardial Necrosis ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Posterior Hypothalamus ◽

Ischemic Heart ◽

Control Structures ◽

Gating Mechanism

The hypothesis tested was that functional blockade of a pathway known to travel from the frontal cortex through the posterior hypothalamus to the brain stem might prevent the occurrence of ventricular fibrillation (VF) in the ischemic heart of conscious stressed pigs. The hypothesis was based on previous findings that 1) psychological stress is a necessary factor for the initiation of VF in the ischemic heart of conscious pigs, 2) the frontal cortex and its related thalamic gating mechanism, uniquely show neuroelectric responses to stressful stimuli, and 3) direct electric stimulation of either the frontal cortex, posterior hypothalamus, or fields of Forel will produce ventricular arrhythmias and myocardial necrosis. In the present study it was found that cryogenic blockade of the forebrain, posterior hypothalamus, or fields of Forel prevents or delays VF after left anterior descending coronary artery occlusion in conscious stressed pigs (P less than 0.01). Blockade of control structures adjacent to these loci in another group of pigs had no effect on VF latency. Neither heart rate nor electroencephalographic changes could explain the differences between the groups. The results show that blockade of the frontocortical-brain stem pathway prevents the lethal consequences of myocardial ischemia in stressed animals.

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Reduction by Propranolol of Myocardial Necrosis following Temporary Coronary Artery Occlusion in Dogs

Circulation Research ◽

10.1161/01.res.33.3.353 ◽

1973 ◽

Vol 33 (3) ◽

pp. 353-363 ◽

Cited By ~ 143

Author(s):

KEITH A. REIMER ◽

MARGARET M. RASMUSSEN ◽

ROBERT B. JENNINGS

Keyword(s):

Coronary Artery ◽

Myocardial Necrosis ◽

Coronary Artery Occlusion ◽

Artery Occlusion

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Reduction of ischemia-induced myocardial necrosis in the rat with permanent coronary artery occlusion under the effect of diltiazem

Journal of Molecular and Cellular Cardiology ◽

10.1016/0022-2828(82)90105-5 ◽

1982 ◽

Vol 14 (1) ◽

pp. 53-62 ◽

Cited By ~ 20

Author(s):

A Zamanis

Keyword(s):

Coronary Artery ◽

Myocardial Necrosis ◽

Coronary Artery Occlusion ◽

Artery Occlusion

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Effect of Acidotic Blood Reperfusion on Reperfusion Injury After Coronary Artery Occlusion in the Dog Heart

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199802000-00002 ◽

1998 ◽

Vol 31 (2) ◽

pp. 179-186 ◽

Cited By ~ 33

Author(s):

Benedikt Preckel ◽

Wolfgang Schlack ◽

Detlef Obal ◽

Holger Barthel ◽

Dirk Ebel ◽

...

Keyword(s):

Coronary Artery ◽

Reperfusion Injury ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Dog Heart

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Movement of necrotic wavefront after coronary artery occlusion in rabbit

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1982.243.5.h682 ◽

1982 ◽

Vol 243 (5) ◽

pp. H682-H690 ◽

Cited By ~ 7

Author(s):

C. Connelly ◽

W. M. Vogel ◽

Y. M. Hernandez ◽

C. S. Apstein

Keyword(s):

Coronary Artery ◽

Left Ventricle ◽

Infarct Size ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Early Reperfusion ◽

Transmural Extent ◽

Circumferential Extent ◽

Tetrazolium Staining ◽

Four Levels

Movement of the necrotic wavefront after coronary artery occlusion (CAO) was defined in rabbits by comparing transient CAO (15, 30, or 60 min) and reperfusion to permanent CAO (n = 5-9/group). At 24 h after CAO the area of necrosis was determined by nitro-blue tetrazolium staining, and the transmural and circumferential extent of necrosis was evaluated at four levels from ligation to apex. Infarct size after permanent CAO for 24 h was 27 +/- 2 (SE) % of the left ventricle. Reperfusion at 60, 30, or 15 min after CAO reduced the infarct size to 24 +/- 3 (P = NS vs. 24 h), 14 +/- 2, and 8 +/- 1% (P less than 0.05 vs. 60 min), respectively. Reperfusion at 15 and 30 min after CAO decreased transmural extent by 49 and 38% (P less than 0.001 vs. 24 h), whereas the circumferential extent was reduced by only 10 and 12%, respectively (P = NS). After 60 min of CAO, reperfusion did not significantly reduce either transmural or circumferential necrosis. Thus early reperfusion reduced infarct size by converting potentially transmural infarcts into subendocardial infarcts but did not significantly reduce the lateral or circumferential extent of necrosis.

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