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Consequences of activation and adenosine-mediated inhibition of granulocytes during myocardial ischemia
Insights
Granulocytes obstruct blood flow during myocardial ischemia and reperfusion, causing no-reflow. Inhibiting granulocytes with adenosine, boosted by AICA-riboside, improves blood flow and prevents injury.
Area of Science:
- Cardiovascular Science
- Inflammation Research
- Cellular Biology
Background:
- Granulocytes accumulate during myocardial ischemia, obstructing microcirculation and causing the no-reflow phenomenon upon reperfusion.
- This granulocyte plug formation significantly limits blood flow and myocardial salvage after ischemic events.
- Inflammatory signals persist during reperfusion, exacerbating tissue damage and hindering recovery.
Purpose of the Study:
- To investigate the role of granulocytes in myocardial ischemia and reperfusion injury.
- To explore the potential of adenosine and AICA-riboside in mitigating granulocyte-mediated no-reflow.
- To test the hypothesis that adenosine acts as a natural anti-inflammatory agent during ischemic injury.
Main Methods:
- Comparison of myocardial perfusion and capillary no-reflow in agranulocytic versus whole blood models during ischemia.
- Measurement of granulocyte content in myocardium using 111In labeling.
- Assessment of collateral blood flow, edema, and arrhythmias in response to AICA-riboside pretreatment in a canine ischemia model.
Main Results:
- Absence of granulocytes prevented no-reflow, increased collateral flow, and reduced edema and arrhythmias.
- AICA-riboside pretreatment significantly augmented adenosine release, enhancing collateral blood flow and decreasing arrhythmias.
- Granulocyte accumulation increased during ischemia and further upon reperfusion, correlating with no-reflow.
Conclusions:
- Granulocytes are key contributors to microcirculatory obstruction and no-reflow during myocardial ischemia and reperfusion.
- Adenosine, augmented by AICA-riboside, shows promise in inhibiting granulocyte activation and improving reperfusion.
- Targeting granulocyte activation is crucial for optimizing tissue salvage and preventing reperfusion injury in acute myocardial ischemia.
Abstract:
During acute myocardial ischemia, granulocytes accumulate and obstruct the microcirculation. Granulocytes remain plugged in individual myocardial capillaries on reperfusion and are the major cause of the no-reflow phenomenon. During 3 h of ischemia, the granulocyte content of myocardium measured by 111In labeling increases from 1.0 X 10(6) to 1.5 X 10(6) cells/g, and after 5 min of reperfusion increases to 2.4 X 10(6) cells/g. The effects of granulocytes during 1 h of acute ischemia were determined by comparing agranulocytic to whole blood perfusion. With whole blood collateral flow decreased, water content increased (edema), ventricular fibrillation was common, and 27% of capillaries had no-reflow, whereas in the absence of granulocytes, collateral flow increased, there was no edema, arrhythmias were rare, and the no-reflow phenomenon was completely prevented. It is unfortunate that the inflammatory signals triggered by ischemia remain active on acute reperfusion, limit tissue salvage, and perhaps cause reperfusion injury. Several activating stimuli for granulocytes are known, but what inhibits them? Adenosine is known to inhibit superoxide radical formation by granulocytes, and 5-amino-4-imidazole carboxamide-riboside (AICA-riboside) augments adenosine release from energy-deprived cells. In dogs subjected to 1 h of ischemia, AICA-riboside pretreatment augmented adenosine release by nearly 10-fold, which was accompanied by a significant increase in collateral blood flow and decreased arrhythmias. We propose a new hypothesis: adenosine acts as a natural antiinflammatory autacoid during transient injury linking the ability to catabolize ATP (an indicator of viability) to granulocyte inhibition, thus preventing premature activation of the inflammatory response to cell death. Granulocytes are active participants in acute myocardial ischemia and means to prevent their activation, remove them from the reperfusate, or inhibit them will be necessary for optimum reperfusion salvage.