EFFECT OF NITRIC-OXIDE DONORS ON NEOINTIMA FORMATION AND VASCULAR REACTIVITY IN THE COLLARED CAROTID-ARTERY OF RABBITS

Intimal thickening in arteries is considered a site of predilection for atherosclerosis. We investigated whether oral application of the nitric oxide (NO) donors SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethylester, 10 mg/kg body weight twice daily (b.i.d.)] and molsidomine (10 mg/kg body weight/day) can retard neointima formation and changes in vascular reactivity induced by a nonocclusive, soft silicone collar positioned around the left carotid artery of rabbits. The contralateral carotid artery was sham operated and served as a control. Drug and placebo (diet without drug) treatments were initiated 7 days before placement of the collar. At the end of the experiments, two segments were cut from each collared and sham-treated artery, one for measurement of the cross-sectional area of intima and media and the other for isometric tension recording. Sham treatment did not result in intimal thickening in either group. In contrast, the intima/media (I/M) ratio was considerably increased after 14 days of collar treatment as a result of neointima formation. Intimal thickening was significantly inhibited by SPM-5185 (I/M ratio 0.05 +/- 0.01 vs. 0.11 +/- 0.02, p < 0.05), but not by molsidomine (0.06 +/- 0.02 vs. 0.08 +/- 0.02, p = 0.49), which is a donor of both NO and superoxide anions. Neither collar nor NO donor treatment altered the area of the media. SPM-5185 did not alter the percentage of replicating smooth muscle cells (SMC) in the media after collar treatment, as demonstrated by their immunoreactivity for proliferating eel nuclear antigen (PCNA). Neointima formation was associated with a decreased sensitivity to acetylcholine (ACh), an increased sensitivity to 5-hydroxytryptamine (5-HT), and a decreased maximum force development to 5-HT and KCl. Despite the significant reduction of intimal thickening, SPM-5185 did not antagonize these collar-induced modifications in vascular reactivity, although a tendency toward normalization of the pD(2) value of ACh in collared arteries was observed. Moreover, SPM-5185 did not lead to cross-tolerance towards nitroglycerin (NTG). Development of a neointima can be inhibited by the NO-donor SPM-5185.