Pharmacological approaches to preserving and restoring coronary endothelial function

There is compelling evidence that the endothelium is critical to normal coronary vascular function and that endothelial dysfunction, generally indicated by an impairment of endothelium-dependent vasodilatation, is an important component of coronary artery disease (CAD). Endothelial cells synthesise and release a number of factors, including prostacyclin, nitric oxide (NO), endothelium-derived hyperpolarising factor (EDHF) and endothelin, which are important in the regulation of vascular tone and the control of platelet and leukocyte adhesion, aggregation and migration. NO appears to be the critical factor in the preservation of normal coronary vascular function and there is a well-established correlation between CAD and an impairment of NO activity. Thus, to preserve endothelial function, drugs have been used to either increase the synthesis of NO, or to decrease its breakdown. Fortuitously, compounds such as the HMG-CoA reductase inhibitors, angiotensin (AT) converting enzyme inhibitors (ACEIs), AT receptor antagonists and oestrogen, which have been introduced into clinical practice because of other beneficial effects, have also been shown to improve coronary endothelial function through a variety of mechanisms. In addition, L -arginine, the substrate for NO synthesis, and the anti-oxidants ascorbate and alpha-tocopherol, are able to increase NO synthesis and bioavailability respectively. Studies in experimental animals strongly support the ability of these agents to enhance the activity of endothelium-derived NO but clinical trials have failed to demonstrate reversal of established CAD. Whether these agents preserve endothelial function and prevent the development of CAD remains to be established.