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Updated: Aug 21, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
Selective Pharmacological Blockade of GPR39 Reduces No Reflow and Infarct Volumes in a Rat Acute Myocardial
Carmen Methner1, Mary Plascencia1, Allura Thompson1
1From the Knight Cardiovascular Institute, Portland, Oregon, USA.
Abstract:
Our aim was to determine whether selective pharmacological blockade of GPR39 by the novel drug, VC108, reduces no reflow (NRV) and infarct (INV) volumes during acute myocardial infarction (AMI). Immuocytochemistry and qPCR of isolated rat cardiac cells as well as immunohistochemistry and western blot of rat myocardium was 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 prior to or during coronary occlusion. Groups 3 and 4 received drug/vehicle 5 min prior to 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 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 reduction in NRV and INV with the drug. The reduction in NRV in all animals was associated with higher tissue pO2 in VC108 compared to vehicle treated animals. Similar results were obtained for INV in only in Group 2 animals. In Group 3 animals direct cardiomyocyte effect of VC108 was seen in 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 prior to reperfusion (the latter being clinically more relevant) both in male and female rats. This effect is not seen after reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation through pericyte and VSMC relaxation. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation.
Insights
The novel drug VC108 effectively reduces infarct and no-reflow volumes in acute myocardial infarction (AMI) models by blocking GPR39. Early administration, before or during reperfusion, is key for its protective effects on cardiac tissue.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Cell Biology
Background:
- GPR39 is implicated in cardiovascular regulation.
- Selective pharmacological blockade of GPR39 may offer a therapeutic strategy for acute myocardial infarction (AMI).
Purpose of the Study:
- To evaluate the efficacy of the novel GPR39 antagonist, VC108, in reducing infarct and no-reflow volumes in an AMI rat model.
- To investigate the timing of VC108 administration for optimal therapeutic benefit.
Main Methods:
- GPR39 expression was confirmed in cardiac cells and myocardium using immunocytochemistry, qPCR, immunohistochemistry, and Western blot.
- Rats underwent 1 hour of coronary occlusion followed by 1 hour of reperfusion, with VC108 or vehicle administered at different time points.
- Readouts included infarct volume (INV), no-reflow volume (NRV), tissue pO2, hemodynamics, and cardiomyocyte apoptosis/necrosis.
Main Results:
- VC108 significantly reduced NRV and INV when administered before coronary occlusion or just prior to reperfusion.
- Administration of VC108 post-reperfusion did not reduce NRV or INV.
- VC108 treatment led to higher tissue pO2 and reduced cardiomyocyte necrosis and apoptosis, indicating direct cardioprotective effects.
Conclusions:
- VC108 is a potent therapeutic agent for reducing myocardial damage in AMI, particularly when administered early.
- The drug's mechanism involves GPR39 blockade, leading to vasodilation and direct cardiomyocyte protection.
- Optimal therapeutic window for VC108 is before or immediately preceding reperfusion.
