MORPHOLOGICAL AND FUNCTIONAL-CHANGES IN CORONARY VESSEL EVOKED BY REPEATED ENDOTHELIAL INJURY IN PIGS

Objective: We examined the morphological changes induced by repeated e ndothelial denudation in coronary artery (CA), as well as functional c hanges in the endothelium-dependent and smooth muscle responses to var ious vasoactive agents during the process of intimal thickening. Metho ds: We observed vascular responses in denuded and non-denuded portions of pig CA while being fed a normal diet (n = 11, N group) or 2% chole sterol diet (n = 25, C group) to intracoronary acetylcholine (ACh), 5- hydroxytryptamine (5-HT), substance P (SP), and isosorbide dinitrate ( ISDN) with and without the nitric oxide synthesis inhibitor N-omega-ni tro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v.) over a period of 8 weeks. Balloon endothelial denudation of the left anterior descending CA was carried out every 2 weeks. Results: In N group, maximum vasoco nstriction was obtained with ACh 2 weeks after the first denudation [2 6 +/- 5% vs. 1 +/- 1% pre-denudation, p < 0.05]. L-NAME did not affect ACh-induced CA diameter changes. Thereafter, the response to ACh was attenuated by repeated denudation in N groups. However, the degree of 5-HT-induced CA narrowing at the denuded portion increased from 7 +/- 4% (0 week) to 88 +/- 8% (8 weeks) (p < 0.05). The changes resulted in severe myocardial ischaemia, and suggested that endothelium-dependent vasodilation was progressively attenuated while hyperreactivity of va scular smooth muscle simultaneously increased. Vasodilation induced by SP was attenuated somewhat, but ISDN-induced vasodilation was preserv ed. Although mild hypercholesterolaemia was induced in C group, the va scular responses to these vasoactive agents did not differ from those of N group. Conclusions: Repeated CA endothelial injury and regenerati on induce the change of morphology and vascular reactivity in the denu ded portion regardless of atherogenic diet. This study strongly sugges ts that intimal thickening caused by repeated endothelial injury and r egeneration induces specific vascular responses to vasoactive agents. Moreover, it is also suggested that during the progression of intimal thickening, increased vascular smooth muscle contraction and decreased endothelium-dependent dilation appear in a stimulus-dependent manner, often leading to severe coronary vasoconstriction accompanied with de finitive ECG ST change. (C) 1998 Elsevier Science B.V. All rights rese rved.