Abstract
ST-segment elevation is the major clinical criterion for committing patients with chest pain to have emergent coronary revascularizations; however, the mechanism responsible for ST-segment elevation is unknown. In a guinea pig model of ST-segment elevation acute myocardial infarction (AMI), local application of hirudin, a thrombin antagonist, significantly decreased AMI-induced ST-segment elevation in a dose-dependent manner. Hirudin-induced (5 antithrombin units [ATU]) decrease in ST elevation was reversed by 250 nmol/L thrombin receptor activator peptide (TRAP). TRAP (250 nmol/L [100 microL]) significantly induced ST-segment elevation in hearts without AMI. The TRAP effect was blocked by 4 mg/kg glibenclamide and 4 mg/kg HMR1098 and partially blocked by 3 mg/kg 5HD. Pinacidil (0.45 mg/kg) simulated the effect of TRAP (250 nmol/L [100 microL]) on hearts without AMI. Moreover, single-channel recordings showed that TRAP induced ATP-sensitive K+ channel (KATP channel) activity, and this effect was blocked by HMR1098 but not 5HD. Finally, TRAP significantly shortened the monophasic action potential (MAP) at 90% repolarization (MAP90) and epicardial MAP (EpiMAP) duration. These effects of TRAP were completely reversed by HMR1098 and partially reversed by 5HD. Thrombin and its receptor activation enhanced ST-segment elevation in an AMI model by activating the sarcolemmal KATP channel.
Highlights
ST-segment elevation is a typical hallmark to diagnose acute myocardial infarction (AMI) and is the major clinical criterion for committing patients with chest pain to emergent coronary revascularizations
Because STsegment elevation is the major criterion for thrombolytic therapy, we aimed to examine the role of thrombin and its receptor activation in ST-segment elevation during AMI
Our studies demonstrated that eliminating endogenous thrombin with hirudin significantly decreased STsegment elevation, which was induced by AMI in our guinea pig model
Summary
ST-segment elevation is a typical hallmark to diagnose AMI and is the major clinical criterion for committing patients with chest pain to emergent coronary revascularizations. In spite of this knowledge, the mechanism of ST-segment elevation remains unclear. Neither theory can explain how the transmural voltage gradient that leads to ST-segment elevation is generated during ventricular repolarization or explain its ionic basis. Potassium current activation is sufficient to cause ST elevation during acute ischemia [1]. Activation of the ATP-sensitive K+ channel (KATP channel) owing to hypoxia is generally hypothesized to result in ST-segment elevation in AMI [2]. Kir6.2 was shown to be responsible for ST-segment elevation in Kir6.2-knockout mice [3]
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