Acute coronary syndrome is a serious medical emergency. It occurs when an atherosclerotic plaque ruptures, leading to thrombus formation within a coronary artery. Previous studies have shown that T cells are involved in the initiation and progression of acute coronary syndrome. CD4(+)CD28(null) T lymphocytes increase in atherosclerotic plaque, and voltage-gated potassium channel Kv1.3 blockers can suppress the function of these cells in vitro by preventing exocytosis of their cytoplasmic granules. The purpose of this study was to investigate the effect of PAP-1, a small molecule voltage-gated potassium channel Kv1.3 blocker, on the development of atherosclerosis (AS) in a rat model and the potential mechanism for this effect. Plasma lipids, interferon gamma, CRP, CD4(+)CD28(null) T cells, and perforin were increased and unstable atherosclerotic plaques developed in the rat model of AS. Blockade of the Kv1.3 potassium channel via PAP-1 administration decreased perforin levels and prevented plaque formation but had no effect on the other changes seen in this AS model. These findings suggest that the small molecule, voltage-gated potassium channel Kv1.3 blocker PAP-1 can suppress the development of AS in a rat model, most likely by inhibiting the exocytosis of cytoplasmic granules from CD4(+)CD28(null) T cells.