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Activation of thrombin receptor increases intracellular Na+ during myocardial ischemia
1Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Insights
Activation of the thrombin receptor by SFLL peptide during myocardial ischemia significantly increases intracellular sodium ([Na+]i) and lysophosphatidylcholine (LPC) levels. This leads to a higher risk of ventricular arrhythmias.
Area of Science:
- Cardiovascular Physiology
- Biochemistry
- Cardiac Electrophysiology
Background:
- Coagulation system activation and intracoronary thrombus formation are implicated in myocardial ischemia-induced arrhythmias.
- The role of specific thrombin receptor activators in modulating ionic and lipid changes during ischemia requires further investigation.
Purpose of the Study:
- To investigate the effect of the thrombin receptor activating peptide SFLL on intracellular sodium ([Na+]i) and lysophosphatidylcholine (LPC) content during acute myocardial ischemia.
- To determine the impact of SFLL-induced changes on arrhythmogenesis in an isolated rabbit papillary muscle model.
Main Methods:
- Utilized an isolated, blood-perfused rabbit papillary muscle preparation.
- Measured intracellular Na+ ([Na+]i) using a Na(+)-selective electrode.
- Quantified tissue lysophosphatidylcholine (LPC) content during normoxia and ischemia.
- Administered SFLL peptide and monitored electrophysiological parameters and arrhythmias.
Main Results:
- SFLL peptide significantly increased [Na+]i during ischemia compared to controls (23.5 +/- 1.9 mM vs. 15.5 +/- 1.4 mM at 6 min).
- SFLL treatment led to greater accumulation of arrhythmogenic LPC in ischemic myocardium.
- The rise in [Na+]i and LPC accumulation was associated with the development of early ventricular arrhythmias.
Conclusions:
- Activation of the thrombin receptor by SFLL exacerbates intracellular sodium ([Na+]i) accumulation during myocardial ischemia.
- This effect is likely mediated by increased lysophosphatidylcholine (LPC) levels, contributing to arrhythmogenesis.
- Thrombin receptor activation may play a crucial role in arrhythmias associated with myocardial ischemia and coagulation system activation.
Abstract:
Recent evidence indicates that factors involved in the activation of the coagulation system eliciting an intracoronary thrombus may contribute importantly to arrhythmogenesis during acute myocardial ischemia. In the present study, the influence of the thrombin receptor activating peptide, SFLLRNPNDKYEPF (SFLL), on intracellular Na+ ([Na+]i) and tissue lysophosphatidylcholine (LPC) content during ischemia was investigated in an isolated, blood-perfused rabbit papillary muscle preparation. During normoxic perfusion, [Na+]i, determined by an intracellular Na(+)-selective electrode, was 11.6 +/- 0.2 mM (n = 14) in the presence of a physiological concentration of LPC (125 microM) bound to albumin (control group). The addition of SFLL (100 microM, n = 12) to the LPC-containing perfusate had no significant additional effects on [Na+]i, twitch tension, action potential duration, or tissue LPC content. During zero flow ischemia, [Na+]i in the control group rose to 15.5 +/- 1.4 mM (P < 0.05) at 6 min, whereas [Na+]i in the group treated with SFLL increased rapidly from the preischemic value of 11.7 +/- 0.3 to 23.5 +/- 1.9 mM (P < 0.01 compared with that in the control group) over the same time period. This rapid rise in [Na+]i was associated with a greater accumulation of tissue LPC, an arrhythmogenic lipid metabolite, and the development of early ventricular arrhythmias. These results indicate that an increase in [Na+]i induced by activation of the thrombin receptor, likely mediated through its effect on the accumulation of LPC within ischemic myocardium, may be responsible for arrhythmogenesis during myocardial ischemia secondary to activation of the coagulation system.