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Restenosis, the major limitation of balloon angioplasty, is the result of intimal hyperplasia after the procedure. Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) inhibitor, may influence intimal hyperplasia by lowering serum cholesterol and by blocking deoxyribonucleic acid (DNA) synthesis. To determine whether lovastatin reduces intimal hyperplasia, a prospective, randomized blinded study was performed in 60 atherosclerotic New Zealand White male rabbits. Atherosclerosis was produced by air desiccation injury followed by a 28 day diet of 2% cholesterol and 6% peanut oil that was terminated before balloon angioplasty was performed. Angioplasty could not be performed in 14 rabbits with bilateral femoral artery occlusion, and in one rabbit the procedure was a technical failure. Forty-five rabbits underwent balloon angioplasty performed with use of a 2.5-mm balloon inflated to 10 atm for three 1 min dilations at 1 min intervals. Seven rabbits died during the procedure. Thirty-eight rabbits were randomized to either a lovastatin group (6 mg/kg body weight per day) or a control group. Angioplasty was performed on all patent vessels (n = 54); the procedure was bilateral in 16 rabbits and unilateral in 22. Fifteen lovastatin-treated and 15 control rabbits survived 39 days after angioplasty and were then killed. Angiograms, obtained before and 10 min and 39 days after balloon angioplasty, were read with use of electronic calipers by two observers who had no knowledge of treatment data. After the rabbits were killed, vessels were pressure perfused using a standardized protocol to maintain in vivo dimensions for blinded quantitative histologic analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

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Vasospasm occurs both in patients and animal models after angioplasty and may be associated with early closure of the dilated vessel. To investigate the mechanism of angioplasty-induced vasospasm, the effect of serotonin-receptor blockade with two serotonin? (SJ antagonists, LY53857 and sergolexole, was examined in rabbits with focal femoral artery atherosclerosis. In preliminary studies, local infusion of 1-100 /ig serotonin caused significant femoral artery vasoconstriction (p<0.05) in both normal and atherosclerotic rabbits. There was no significant difference in the degree of vasoconstriction induced by equal doses of serotonin in normal and atherosclerotic animals. Infusion of 10 fig serotonin produced a 23 ±5% decrease in luminal diameter in atherosclerotic femoral arteries. This was blocked by pretreatment with both S 2 inhibitors given separately in different animals before serotonin infusion (/?< 0.002). In contrast, LY53857 (sergolexole was not tested) had no significant effect on phenylephrineinduced vasoconstriction, confirming its specificity as an S^-receptor antagonist Balloon angioplasty of atherosclerotic vessels caused a significant increase in vessel diameter at the angioplasty site (45% increase from baseline diameter, p<0.05). This was associated with significant luminal narrowing both proximal (21% redaction from baseline, p<0.05) and distal (17% reduction from baseline, p<0.03) to the angioplasty site. These proximal and distal changes are most likely due to vasospasm, as there was no histological evidence of thrombus or dissection at these sites to explain the luminal narrowing. Pretreatment of animals with 10 mg LY53857 or 20 mg sergolexole blocked the proximal vasospasm (2.6±0.4 before versus 2.2±0.1 mm after angioplasty for LY53857, 2.1 ±0.4 before versus 2.1 ±0.4 mm after angioplasty for sergolexole; p=NS). Treatment with 20 mg LY53857 inhibited both proximal (2J±0.1 before versus 2.2±0.2 mm after angioplasty, p=NS) and distal (1.7±0.1 before versus 1.6±0.2 mm after angioplasty, p=NS) vasospasm after angioplasty. Proximal (2.3 ±0.5 before versus 2.5±0.3 mm after) and distal (1.7±0.2 before versus 1.7±0.4 mm after) vasospasm was also prevented by pretreatment with 40 mg sergolexole. We conclude that 1) serotonin-induced vasoconstriction in normal and atherosclerotic rabbit femoral arteries is mediated in part by Sj receptors since it can be blocked by the specific antagonists LY53857 and sergolexole; 2) the specificity of LY53857 action is confirmed by its lack of inhibition of