REGIONAL VARIATIONS IN ENDOTHELIN-1 AND ITS RECEPTOR SUBTYPES IN HUMAN CORONARY VASCULATURE - PATHOPHYSIOLOGICAL IMPLICATIONS IN CORONARY-DISEASE

Endothelin-1 is a potent vasoconstrictor peptide and mitogen for vascu lar smooth muscle cells. Increased plasma or tissue levels of endothel in-1 have been described after myocardial infarction and in atheroscle rosis, suggesting that this peptide may play a pathophysiological role in various coronary syndromes. Here, we have studied regional variati ons in ET-1 and its receptors in control and atherosclerotic human cor onary vasculature using standard immunohistochemistry and in vitro aut oradiography. ET-1 immunoreactivity was associated with luminal endoth elial cells and smooth muscle cells at regions of atherosclerosis. ET( A)receptors were present on smooth muscle cells of coronary arteries a nd on cardiac myocytes. Medial ETB receptor binding at the proximal re gion of coronary arteries was weak, but increased significantly toward s distal regions of this vessel (p>0.005 in control and p<0.0005 in is chaemic heart disease). Microvascular endothelial cells in the adventi tia of coronary arteries, myocardial microvessels and the endocardial endothelium expressed the ETB receptor exclusively. The receptor varia tions revealed in this study provide supporting evidence that ET-1 is associated with (I) vascular smooth muscle and endothelial cell prolif eration, including areas of intimal hyperplasia and regions of neovasc ularization (2) increased ET-l-induced reactivity of distal portions o f the human coronary artery, (3) ET-l-mediated constriction of myocard ial microvessels. These results provide new insights into different po tential roles for this peptide in healthy and diseased human coronary vasculature.