Vascular protection: current possibilities and future perspectives

Endothelial cells are strategically located between the circulating blood and the vascular smooth muscle. These cells are involved in regulating the functions of vascular smooth muscle and circulating blood cells by releasing numerous vasoactive substances. Important endothelium-delivered vasodilators include prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarising factor. Nitric oxide is also important in inhibiting cellular growth and migration, and acts in concert with prostacyclin to exert potent antiatherogenic and thromboresistant effects by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors such as angiotensin II and endothelin-1, which exert prothrombotic inflammatory and growth-promoting properties. Cardiovascular risk factors give rise to cardiovascular disease by causing endothelial dysfunction. Consequently, modern therapeutic strategies focus on preserving or restoring endothelial integrity. Calcium antagonists counteract the effects of angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. In addition to their role in inhibiting the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors raise the activity of bradykinin, thereby leading to an increase in nitric oxide release. In patients with cardiovascular risk, chronic ACE inhibition improves endothelial function. This may explain why patients treated with ACE inhibitors experience a greater cardiovascular benefit than is attributable to the decrease in blood pressure. Recently developed neutral endopeptidase inhibitors, particularly in combination with ACE inhibitors, induce potent antihypertensive effects. These effects are due partly to decreased breakdown of natriuretic peptides but also as a result of the inhibition of endothelin-1 production. Experimental studies suggest that endothelin-1 antagonists are effective in lowering blood pressure in hypertensives, and also exert beneficial clinical and haemodynamic effects in patients with congestive heart failure. Further clinical studies are under way to determine whether restoration of endothelial function has clinical benefits for patients with cardiovascular disease.