Local Application of Calcium Antagonists Inhibits Intimal Hyperplasia after Arterial Injury

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Abstract

ABSTRACT

THE LOCAL EFFECT of the calcium channel antagonist diltiazem and the protein kinase inhibitor 1–5-(isoquinoline sulfonyl)-5-homopiperazine HCL (HA1077) on neointimal formation after arterial injury were investigated by the use of a perivascular drug-delivery system. Bilateral carotid artery balloon injury was produced in 130 rats. In six groups of 10 rats each, diltiazem or HA1077 at three doses (low, 0.2 mg; medium, 1 mg; high, 5 mg) was mixed with the drug-delivery polymer poly(vinyl) alcohol and applied to the adventitial surface of the injured right carotid artery enclosed by a Silastic cuff; 10 control animals received polyvinyl alcohol only in the silastic cuff. In all animals, the contralateral injured artery without the cuff served as a control. At 10 and 20 days after the injury, the intimal cross-sectional area was determined from light microscopic sections for the injured segment of both carotid arteries. In six additional groups of 10 rats each, treated as above, levels of diltiazem and HA1077 in plasma were measured at periods from 1 hour to 5 days after perivascular application. At 10 days after endothelial injury, animals receiving high-dose diltiazem or HA1077 (5 mg) demonstrated significant reductions in neointimal area compared with polyvinyl alcohol controls for both treated and contralateral untreated vessels. At 20 days after injury, neointimal hyperplasia was inhibited only on the treated side in both high-dose groups. Perivascular diltiazem and HA1077 at lower doses (1 or 0.2 mg) did not affect neointimal area at 10 or 20 days in either treated or untreated arteries. In both high-dose groups, drug levels in plasma were at or greater than the therapeutic range from 1 hour to 1 day after application, whereas subtherapeutic levels were present within 1 hour after the application at a low or moderate dose. The application of both agents to the arterial wall at a high dose probably inhibited neointimal formation after arterial injury by both short-term systemic effects and longer term localized effects on the vessel wall.

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