NITRIC-OXIDE IN ATHEROSCLEROSIS - VASCULAR PROTECTOR OR VILLAIN

1. Nitric oxide (NO) has important roles in physiological vasodilatati on, cytotoxicity and vascular disease. Nitric oxide and prostacyclin ( PGI(2)), both released from the endothelium, act synergistically to in hibit platelet aggregation and adhesion. These autacoids also inhibit the adhesion and migration of leucocytes and, in some arteries, they s ynergize in terms of vasodilatation. 2. The development of atheroscler osis and hyperlipaemia per se is accompanied by impairment of endothel ium-dependent vasodilatation, 3. Atherosclerosis is associated with ma rked changes in the activity of isoforms of NO synthase (NOS) in the a rtery wall, including increased expression of the NOS2 (inducible) iso form in complex human lesions as well as in the neointima of experimen tal animal models. 4. Failure of NO release from the endothelium with normal physiological stimuli, which has been attributed to a defect in the operation of the endothelial NOS (NOS3), provides conditions prop itious for leucocyte adhesion, vasospasm, thrombosis and, in addition, mag promote increased proliferation of intimal cells. 5. Nitric oxide and superoxide anions generated by inflammatory cells in atherosclero sis react to form cytodestructive peroxynitrite radicals, potentially causing injury to the endothelium and myocytes, and this may be a fact or in apoptosis of cells leading to plaque rupture. 6. We have been ab le to reverse these NO defects with therapeutic agents, including angi otensin-converting enzyme inhibitors, antagonists of platelet-activati ng factor and NO donor compounds, all offering promise in protecting a gainst some manifestations of vascular disease.