Endothelin and angiotensin II receptors in human coronary arteries and bypass grafts - Alterations in cardiovascular disease

Sammanfattning: Angiotensin II (Ang II) and endothelin-1 (ET-1) induce strong vasoconstriction via activation of receptors on vascular smooth muscle cells. In this thesis, the contractile Ang II and endothelin receptors were examined in endothelium-denuded human coronary arteries and in bypass grafts (the left internal mammary artery and the saphenous vein), with focus on receptor alterations in cardiovascular disease. The endothelium was removed and the vasomotor responses were characterized by in vitro pharmacology and the receptor mRNA expression levels were quantified by real-time polymerase chain reaction. Vasoconstriction was mediated by endothelin type A (ETA) receptors in coronary arteries, while both ETA and endothelin type B (ETB) receptors were involved in the bypass grafts. The ETB receptor-mediated contraction and mRNA levels were higher in the saphenous vein than in the mammary artery. This may explain the higher frequency of vasospasm that is seen in the vessel wall of the saphenous vein at the time of surgery and restenosis due to “venous graft disease”. The ETA and ETB receptor mRNA levels were up-regulated in coronary arteries from patients with ischemic heart disease. Increased endothelin receptor activity may contribute to the smooth muscle cell proliferation, vasoconstriction and the decreased blood perfusion that is noted in atherosclerotic disease. The Ang II-induced vasoconstriction of endothelium-denuded human coronary arteries is caused by activation of angiotensin type 1 (AT1) and, to a lesser extent, angiotensin type 2 (AT2) receptors. AT1 receptor mRNA levels were decreased both in arteries from patients with ischemic heart disease and patients with heart failure due to other causes. In patients with heart failure, both the Ang II-induced contraction and the AT1 receptor mRNA levels diminished with increasing age, which may be due to a longer exposure to heart failure in older patients. Culture of human coronary arteries induced similar Ang II and endothelin receptor changes as in ischemic heart disease and heart failure. The Ang II induced contraction and the AT1 and AT2 receptor mRNA levels were decreased, while the ETB receptor mediated contraction and mRNA levels were increased. Organ culture may therefore provide an experimental method in which the development of Ang II and endothelin receptor changes on smooth muscle cells can be studied in detail to further delineate the mechanisms involved in receptor regulation during ischemic heart disease and heart failure.