Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Model of Acute...

Our aim was to determine whether selective pharmacological blockade of GPR39 by the novel drug, VC108, reduces no reflow (NRV) and infarct (INV) volumes acute myocardial infarction (AMI). Rats underwent 1 h of coronary occlusion and 1 h of reperfusion. Groups 1 and 2 animals received drug/vehicle prior to or during coronary occlusion. Group 3 received drug/vehicle 5 min prior to reperfusion. Readouts also included tissue pO₂, hemodynamics, and wall thickening. In Groups 4 and 5 animals, drug was injected for measurement of plasma and tissue levels. Immunohistochemistry and western blot of rat myocardium as well as immuocytochemistry and qPCR of cardiac cells was performed for presence of GPR39. There was marked reduction in NRV and INV in groups 1 and 3 animals where both were measured and in Group 2 where INV was measured. The reduction in NRV in all animals was associated with higher tissue pO₂ during VC108 compared to vehicle. Similar results were obtained for INV in Group 2 animal, but not in Groups 1 and 3. Immunohistochemistry and western blot of heart tissue as well as immunocytochemistry and qPCR of cells revealed high expression of GPR39 in cardiomyocytes, a hithertofore unknown finding. We conclude that VC108 is very effective in reducing INV and NRV in a rat AMI model when given before coronary occlusion or just prior to reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation by relaxing pericytes and VSMCs. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation.