Vascular Endothelial Function and ACE Inhibition

Endothelial cells line the entire inner surface of the vasculature providing a smooth interface between circulating blood and the vessel wall, as well as mediating crucial metabolic functions. As a rich source of vasoactive substances, the endothelium plays a role as an organ system with autocrine, paracrine, and even endocrine functions regulating vascular tone, regional blood flow, and intimal proliferation. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor. These substances have a major role in the evolving concept of early atherosclerosis, as well as that of stable and unstable ischemic syndromes (21).

The predominant tone of a vascular bed is the sum of simultaneously acting vasodilator and vasoconstrictor influences. In normally functioning endothelial cells, a basal rate of production of NO is maintained by the action of the constitutive enzyme NO synthase (22). This basal production, which requires a normal endothelium, maintains a net vascular relaxation. However, various vasoactive substances (i.e., bradykinin, serotonin, adenosine diphosphate, and substance P), as well as the effect of blood's shearing force on the endothelium, can up-regulate NO synthase activity, increasing production and secretion of NO (23-25). NO inhibits cellular growth and migration. In concert with prostacyclin, NO exerts potent anti-atherogenic and antithrombotic properties by preventing platelet aggregation and cell adhesion (21).

The renin-angiotensin system influences endothelial function, and there is evidence that ACE inhibition may improve endothelial function through multiple possible mechanisms. Mancini and co-workers (26) reported on 129 patients with documented coronary atherosclerosis randomized to quinapril or placebo for 6 mo. Coronary endothelial function was assessed with intracoronary infusions of acetylcholine. Quinapril-treated patients had an improvement in endothelial function, when compared to placebo-treated patients. The authors postulated that among other causes, decreased degeneration of NO, and bradykinin-mediated NO release may also play a part.

More recently, Takashi et al. (27) have investigated the potential role of the interactions of ACE inhibitors containing a sulfhydryl (SH) group. Using in vitro techniques that included preparation of human coronary vessels with either nitroglycerin or nicorandil, the investigators studied the effects on the vessels after the addition of either captopril (a SH-group-containing ACE inhibitor) or enalaprilat. Both nitroglycerin and nicorandil exhibited an increase in vasodilatation in the presence of captopril and not in response to enalaprilat. The response may involve the opening of an ATP-sensitive potassium channel and subsequent guanylate cyclase activation. Buikema et al. (28) studied the effects of SH-containing zofenopril vs lisinopril (no-SH group). They found that ACE inhibition with a SH group has a potential advantage in the improvement of endothelial dysfunction through increased activity of NO after release from endothelium. Thus, improvement in endothelial function is an additional possible mechanism to explain the net benefits of ACE inhibitors after and during acute coronary syndromes, in particular MI.

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