Rationale: GsMTx4 peptide is a selective inhibitor of cation selective mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. However, the role of MSCs in ischemic reperfusion injury was unknown. Cation imbalance appears to be a major contributor to ischemic reperfusion injury across multiple systems. MSCs may be significant contributors to the cation overload, and they are likely to be activated in reperfusion due to inhomogeneous local stresses and compromised mechanical support of the sarcolemma.
Objective: The aim of this study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant during ischemia/reperfusion in mice.
Methods and Results: GsMTx4-D pharmacokinetics in the plasma and heart was monitored over 24 hrs using an LCMSMS assay. Ischemia and reperfusion in the mouse heart involved ligating a coronary artery for 20 min followed by release of the ligature. GsMTx4-D was administered by either acute intravenous injection during the ischemic event, or a day prior to the event with two days of intraperitoneal injections, once per day. Dosing of GsMTx4-D was adjusted to achieve tissue concentrations of 1-5 μM. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by >40% for both acute and pretreated animals. Cardiac output was indistinguishable between sham-treated control hearts and GsMTx4-D pretreatment, and arrhythmias were also significantly reduced by intravenous injections of GsMTx4-D.
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 was not toxic and promises to be a useful therapy in reperfusion of the heart and other organs.