Long-Term Treatment of Atherosclerotic Minipigs with Isosorbide Dinitrate Restores Nitric Oxide Release from Endothelial Cells, and Inhibits Vascular Smooth Muscle Cell Proliferation

Vascular smooth muscle cells (VSMCs) activation and hyperplasia, the important etiologic factors in atherosclerosis development, are inhibitable by drugs which donate nitric oxide (NO). We tested the hypothesis that administration of ISDN (60 mg/day), a NO donor, would inhibit development of vascular hyperplasia in atherosclerotic minipigs. VSMC proliferation and NO release by endothelial cells (ECs) were investigated in freshly isolated cells from minipigs fed an atherogenic diet with oral ISDN treatment (n = 8) or without (n = 8), or a control diet (n = 8) for 4 months. In ECs, atherosclerosis depressed by 60% NO release and suppressed the L-arginine negative regulatory feedback of the NO-synthase. Concomitantly, a 4-fold increased proliferation (PCNA labelling) and a 2.3-fold activation (PDGF-BB labelling) were observed in atherosclerotic VSMCs. Long-term treatment of atherosclerotic animals with ISDN restored NO release and regulatory processes of NO synthase from ECs, and reduced by half the proliferation and the activation down to control levels in VSMCs. These data demonstrate that ISDN attenuates intimal hyperplasia and suggest this effect is NO dependent.