Protective Effect of Beraprost Sodium, a Stable Prostacyclin Analogue, on Cardiac Allograft Vasculopathy in Rats

Intimal thickening and luminal narrowing of the coronary arteries are insidious complications of cardiac allograft. However, the pathogenesis of cardiac allograft vasculopathy (CAV) remains to be clarified. In this study, the protective effect of a prostacyclin analogue (beraprost sodium; BPS) on CAV was evaluated after heterotopic cardiac transplantation in rat. All recipients were treated with cyclosporine A (10 mg/kg/day intramuscularly). Eight rats received oral therapy with BPS of 50 μg/kg/day (BPS group) and another 8 rats received vehicle only (control group). All surviving cardiac grafts were removed on the 60th postoperative day and were examined to determine the severities of cellular rejection and CAV (>50 μm in diameter). Additionally, 6-keto-prostagrandin Fla and thromboxane B2 were compared between the two groups. There was no significant difference in the grading score for cellular rejection based on the ISHLT grading system (2.31 ± 0.75 vs 2.47 ± 0.65, p=0.81). Although the endothelial cells were preserved in both groups, a deposition of fibrin-like dense materials was recognized in the subendothelial layers of the control group, but not in the BPS group. Intimal thickening was inhibited significantly in the BPS group. The intimal ratio (intimal area/sectional area of artery) was significantly lower in the BPS group than in the control group (0.134 ± 0.03 vs 0.205 ± 0.047; p<0.01), without any difference in the medial ratio (medial area/sectional area of artery). a-actin positive smooth muscle cells (SMC) in intima were fewer in number in the BPS group than in the control group. The plasma thromboxane B2 level was significantly lower in the BPS group than in the control group (270 ± 116 pg/ml vs 585 ± 258 pg/mg; p<0.01). It was concluded that BPS suppressed CAV development after heterotopic allogenic cardiac transplantation in rats.