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 fo r atherosclerosis. We investigated whether oral application of the nit ric oxide (NO) donors SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)- cysteine ethylester, 10 mg/kg body weight twice daily (b.i.d.)] and mo lsidomine (10 mg/kg body weight/day) can retard neointima formation an d changes in vascular reactivity induced by a nonocclusive, soft silic one collar positioned around the left carotid artery of rabbits. The c ontralateral 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 se gments were cut from each collared and sham-treated artery, one for me asurement of the cross-sectional area of intima and media and the othe r for isometric tension recording. Sham treatment did not result in in timal 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 no t alter the percentage of replicating smooth muscle cells (SMC) in the media after collar treatment, as demonstrated by their immunoreactivi ty for proliferating eel nuclear antigen (PCNA). Neointima formation w as associated with a decreased sensitivity to acetylcholine (ACh), an increased sensitivity to 5-hydroxytryptamine (5-HT), and a decreased m aximum force development to 5-HT and KCl. Despite the significant redu ction of intimal thickening, SPM-5185 did not antagonize these collar- induced modifications in vascular reactivity, although a tendency towa rd normalization of the pD(2) value of ACh in collared arteries was ob served. Moreover, SPM-5185 did not lead to cross-tolerance towards nit roglycerin (NTG). Development of a neointima can be inhibited by the N O-donor SPM-5185.