Abstract 11804: GsMTx4-D is a Cardioprotectant Against Myocardial Infarction During Ischemia and Reperfusion

Abstract

Introduction: GsMTx4 is a selective inhibitor of cationic mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. Inhomogeneous local mechanical stresses due to hypercontracture and swelling, likely induce elevated MSC activity that can contribute to the cation imbalance observed during ischemic reperfusion injury. This study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant during ischemia and reperfusion and to evaluate its effects on cation influx and inflammatory kinases that are regulated by this influx. Hypothesis: GsMTx4 protects heart from ischemic insults through inhibiting the cationic mechanosensitive ion channels. Methods: Ischemia and reperfusion in the mouse heart involved ligating a coronary artery followed by release of the ligature. Results: GsMTx4-D was administered by acute intravenous injection during the ischemic event. Based on pharmacokinetic studies, GsMTx4-D dosage was set to achieve expected plasma concentrations between 50-5000 nM and heart tissue concentrations between 1-200 nM. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by ~40% for acute and pretreated animals, and for both 20 and 45 min ischemic challenges. Many indicators of cardiac output were indistinguishable from sham-treated control hearts after GsMTx4-D treatment and most showed improvement at both 4 and 48 hrs post ischemia. Premature ventricular beats immediately following reperfusion were also significantly reduced by intravenous injections of GsMTx4-D. Myocytes cultured under hypoxic conditions treated with 10 μM GsMTx4-D showed improved contractility and near normal contraction-related Ca 2+ influx. GsMTx4-D inhibited indicators of ischemic damage such as the apoptotic signaling system JNK/c-Jun, but also inhibited the energy response signaling system Akt kinase. Conclusions: GsMTx4-D is a potent cardioprotectant that decreases infarct area, increases cardiac output and decreases arrhythmias that are caused by ischemia and reperfusion. GsMTx4-D improved cardiomyocyte function and suppresses apoptosis, making it potentially useful in multidrug strategies to treat ischemic heart disease.