Selective pharmacological blockade of GPR39 markedly reduces no-reflow and infarct volumes in rat acute myocardial infarction when administered before reperfusion.

Our aim was to determine whether selective pharmacological blockade of G protein-coupled receptor 39 (GPR39) by the novel drug, VC108, reduces no-reflow (NRV) and infarct (INV) volumes during acute myocardial infarction (AMI). Immunocytochemistry and quantitative polymerase chain reaction (qPCR) of isolated rat cardiac cells as well as immunohistochemistry and Western blot of rat myocardium were performed for presence of GPR39. Rats underwent 1 h of coronary occlusion and 1 h of reperfusion. Groups 1 and 2 animals received drug/vehicle before or during coronary occlusion. Groups 3 and 4 received drug/vehicle 5 min before or 30 min after reperfusion. Readouts also included tissue Po2, hemodynamics, and wall thickening. In groups 5 and 6 animals, drug was injected for measurement of plasma and tissue levels. Immunocytochemistry and qPCR of cells and immunohistochemistry and Western blot of tissue revealed GPR39 expression in all cardiac cells analyzed as well as entire myocardial tissue. There was a marked reduction in NRV and INV in groups 1 and 3 animals where both were measured and in group 2 where INV was measured. In contrast, group 4 animals failed to show a reduction in NRV and INV with the drug. The reduction in NRV in all animals was associated with higher tissue Po2 in VC108-treated compared with vehicle-treated animals. Similar results were obtained for INV in group 2 animals. In group 3 animals, a direct cardiomyocyte effect of VC108 was seen in the myocardium as evidenced by reduced necrosis and apoptosis. We conclude that VC108 is very effective in reducing INV and NRV in an AMI model when given before coronary occlusion or just before reperfusion (the latter being clinically more relevant) in both male and female rats. This effect is not seen after reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation through pericyte and vascular smooth muscle cell (VSMC) relaxation. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation.NEW & NOTEWORTHY GPR39 is the receptor for 15-HETE, which is a vasoconstrictor with direct cardiomyocyte detrimental effects. Pharmacological inhibition of GPR39 by a novel inhibitor, VC108, reduces coronary no-reflow after acute myocardial infarction by relaxing contracted pericytes surrounding capillaries, whereby increasing oxygen delivery. GPR39 inhibition also reduces necrosis and apoptosis by interrupting aberrant downstream signaling responsible for cell death. Hence, pharmacological inhibition of GPR39 by VC108 offers a novel treatment of acute myocardial infarction.