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(Circulation. 1996;94:240-243.)
© 1996 American Heart Association, Inc.

Articles

Reversing Endothelial Dysfunction With ACE Inhibitors

A New TREND?

Sanjay Rajagopalan, MD; David G. Harrison, MD

the Division of Cardiology, Emory University School of Medicine (S.R., D.G.H.), and Veterans Administration Hospital (D.G.H.), Atlanta, Ga.

Correspondence to David G. Harrison, Professor of Medicine, Cardiology Division, Emory University School of Medicine, Atlanta, GA 30322. (Circulation. 1996,94:240-243.)

Key Words: Editorials • endothelium-derived factors • vasoconstriction • vasodilation

	Introduction

Top Introduction References

 
During the past 15 years, it has become apparent that the vascular endothelium plays a crucial role in modulating vasomotor tone. The endothelium accomplishes this by synthesizing and releasing several vasoactive substances, including prostacyclin, adenine nucleotides, kinins, NO·, an as-yet-unidentified hyperpolarizing factor, and vasoconstrictor substances such as endothelin, vasoconstrictor prostanoids such as PGH₂, and the superoxide anion (·O₂^-).^{1 2 3} Among the best characterized and likely the most important of these is NO·, which was previously known as EDRF.⁴ NO is produced by the endothelium when a variety of neurohumoral, paracrine, and pharmacological stimuli act on endothelial cell receptors to increase intracellular calcium, which ultimately activates endothelial cell NO synthase. This enzyme catalyzes the complex oxidation of one of the guanidino nitrogens of arginine to NO·.⁵ There is substantial evidence that NO· may be transported attached to other molecules, such as nitrosothiols, both between cells and in the plasma.^{6 7} Vascular smooth muscle cells possess receptors to many of the same agonists that activate NO· release from the endothelium. Thus, the ultimate effect of any given stimulus for NO· release is a balance between the vasodilator effect of NO· versus the direct vasoconstrictive effect of the stimulus on the vascular smooth muscle.

A clinically important aspect of this important role of the endothelium is that it is impaired in a variety of diseases and conditions. These include hypertension, hypercholesterolemia, diabetes, transplant atherosclerosis, congestive heart failure, and cigarette smoking. NO· has a variety of beneficial, potentially antiatherogenic effects in the vessel wall. These include inhibition of platelet aggregation, leukocyte adhesion, and inhibition of adhesion molecule expression. It is conceivable, therefore, that loss of an NO· effect in various disease conditions could contribute to the atherosclerotic process. On the basis of these considerations, there is considerable interest in developing treatment strategies to prevent the loss of endothelial NO· in these various disease states. If this could be accomplished, it has been reasoned that many of the early events in atherosclerosis could be prevented.

In this issue of Circulation, Mancini et al⁸ present a paper that examines the effectiveness of one such treatment strategy. These investigators examined a subgroup of patients with several risk factors that have been associated with loss of endothelial NO·. These patients all had established coronary atherosclerosis, and some had mild hypercholesterolemia. Some were active smokers, and more than half had a history of hypertension. The authors examined responses to intracoronary injections of acetylcholine and nitroglycerin at baseline and after 6 months of treatment with the ACE inhibitor Quinapril or placebo. Acetylcholine was chosen as a prototypical endothelium-dependent vasoactive agent, and nitroglycerin was used as an endothelium-independent vasodilator. In point of fact, in most human studies (as in the present study by Mancini et al), acetylcholine predominantly produces vasoconstriction via its direct action of muscarinic receptors on the vascular smooth muscle. This degree of constriction is blunted by the concomitant release of NO·. Therefore, the lack of constriction or presence of mild vasodilatation of a coronary artery during injection of acetylcholine can be used as a readout for the preserved release of NO·. In contrast, the development of vasoconstriction would indicate a deficiency in NO· release and a direct effect of acetylcholine on the vascular smooth muscle. In the present study, Mancini et al observed a 9% to 14% vasoconstriction in response to the highest dose (10^-4 mol/L) of acetylcholine at the time of initial study. At the 6-month follow-up, the response of the placebo group had not changed (9.4% to 10.5% constriction at baseline and follow-up, respectively), whereas the group treated with Quinapril exhibited a dramatic decrease in the vasoconstriction caused by acetylcholine (from 14.3% to 2.3% constriction at baseline and follow-up, respectively). About twice as many patients in the Quinapril group as in the placebo group exhibited dilation to acetylcholine at the time of follow-up. Responses to nitroglycerin were not changed in either the Quinapril or placebo groups from baseline to follow-up study. The authors concluded that ACE inhibition has a beneficial effect on endothelium-dependent regulation of vasomotion.

This study⁸ has several strengths. An impressively large number of patients was included, particularly for a study as time- and labor-intensive as this, and it is unlikely that the result could be attributed to any artifact resulting from an insufficient number of subjects. Studies such as this are difficult to perform because they involve a repeat catheterization and the protocols are time-consuming for the investigators and the subjects. The analyses of coronary artery diameter involved state-of-the-art quantitative techniques, and the investigators examined both a mild stenosis and other segments of the coronary arteries. Rather than using only the baseline values as a control, the investigators included a placebo-treated group. The effect of Quinapril treatment on the acetylcholine response was substantial, as great as has been reported for lipid lowering.⁹ A potential criticism of the study is that it is not clear whether another vasodilator-like drug could have the same effect. The dose of Quinapril chosen, however, had no effect on blood pressures in these subjects (who primarily were normotensive at the outset), and therefore it is unlikely that this result was simply due to vasodilation. This suggests that ACE inhibition likely has an interaction with the endothelial/NO· system that is independent of a vasodilator or hemodynamic effect.

How could an ACE inhibitor or angiotensin II modulate the ability of the endothelium to release NO·? One well-documented phenomenon relates to the fact that the angiotensin I–converting enzyme and the endothelial cell kininase are one and the same enzyme.¹ As a kininase, this enzyme is responsible for degradation of bradykinin. ACE inhibitors such as Quinapril, therefore, are capable of prolonging the half-life of any bradykinin that is in the proximity of the endothelium. Bradykinin is a potent stimulator of NO· and prostacyclin release. Therefore, an ACE inhibitor theoretically can promote release of these vasodilator substances by augmenting the effect of any bradykinin that is present.¹⁰ It is unclear how important this is in the intact human or animal. It is questionable whether or not there is sufficient bradykinin in proximity to the endothelium under normal circumstances to permit this effect. Furthermore, it is unlikely that prolonging the half-life of bradykinin (even if sufficient quantities of bradykinin were present) could enhance acetylcholine stimulation of NO· release. Thus, although this role of ACE inhibitors has been the focus of substantial investigation, it probably was not the mechanism underlying the beneficial effect observed in the study by Mancini and coworkers.⁸

Angiotensin II is one of the most potent vasoconstrictors produced in vivo. In addition, angiotensin II has been shown to stimulate transcription of preproendothelin and to promote the release of endothelin-1 from vascular cells.¹¹ In renovascular hypertension, angiotensin II has been implicated in stimulating production of the vasoconstrictor prostanoid PGH₂ by the endothelium.¹² An ACE inhibitor such as Quinapril, therefore, could improve vasomotor function by reducing these vasoconstrictor influences. However, it is difficult to understand how this would specifically improve responses to endogenously released NO· and not affect responses to nitroglycerin. Baseline coronary diameters were not different before and after Quinapril treatment, which suggests it was unlikely that Quinapril worked by simply reducing vasoconstrictor influences.

These considerations suggest that ACE inhibition had a unique effect on NO· synthesis and release or on its ultimate effect on the vascular smooth muscle. One potential mechanism to explain this might relate to an increase in expression of the NO synthase enzyme. Although this enzyme has been considered to be expressed constitutively, it is now clear that its expression is subject to modest degrees of regulation. Recent studies¹³ have shown that NO synthase expression can be modulated by shear stress, oxidized LDL, lysophosphatidyl choline, hypoxia, and manipulation of activity of protein kinase C. The latter may have relevance to the effect of an ACE inhibitor, because angiotensin II is a potent activator of protein kinase C.

A mechanism by which an ACE inhibitor very likely could improve the endothelial NO· effect is through modulation of vascular superoxide (·O₂^-) production. Even before the chemical nature of EDRF was identified, it was known that its half-life was prolonged by SOD and shortened by chemical generation of superoxide anions (·O₂^-).¹⁴ This interaction between superoxide and NO· was demonstrated initially in systems in which the ·O₂^- was produced artificially. Several conditions in experimental animals have been found in which vascular ·O₂^- production is increased and that seem to impair endothelium-dependent vascular relaxation via inactivation of NO·.³

One of the most important observations in the past few years regarding vascular sources of ·O₂^- is that both the endothelium and vascular smooth muscle contain membrane-bound oxidase(s) that use NADH and NADPH as substrates for electron transfer to molecular oxygen.¹⁵ These are likely multicomponent enzyme systems that are membrane bound and extramitochondrial. They have similarities to the neutrophil NADPH oxidase in that they possess flavin- and heme-binding regions that probably are important in the transfer of electrons. Recently, Fukui and coworkers¹⁶ cloned a component of the vascular smooth muscle oxidase, p22phox, which has 90% similarity to the neutrophil oxidase system. Thus, at least one component of the vascular oxidase system is similar to the neutrophil system. There are, however, very important differences between the vascular oxidases and the neutrophil oxidase. First, the output of the vascular oxidase is much lower than that of the neutrophil oxidase (nanomoles versus micromoles of ·O₂^- per minute per milligram of protein). Second, the vascular oxidase does not exhibit bursts of activity, as does the neutrophil system, but releases ·O₂^- constantly. This does not detract from the importance of the vascular oxidase system. The neutrophil oxidase system serves a bactericidal role, whereas the vascular oxidase may have other roles, such as modulation of the vasodilator effect of NO·.

An important observation regarding the vascular NADH/NADPH oxidase is that its activity can be increased by angiotensin II. In studies of cultured vascular smooth muscle cells, Griendling and coworkers¹⁷ have shown that subnanomolar concentrations of angiotensin II increase NADH oxidase activity by severalfold in as little as 4 hours. The signaling processes involved seem to be related to activation of phospholipase A₂ and could be mimicked by treatment of cellular homogenates with arachidonic acid.

Recently, we¹⁸ have performed studies to determine whether angiotensin II can activate NADH-driven oxidases in vivo. Osmotic minipumps were used to infuse either angiotensin II (0.7 mg·kg^-1·d^-1) or norepinephrine (2.75 mg·kg^-1·d^-1). Both angiotensin II and norepinephrine increased blood pressure to a similar extent (190 mm Hg). Interestingly, vascular ·O₂^- production was doubled in rats made hypertensive by angiotensin II but was not changed in the rats made hypertensive by norepinephrine infusion. Studies of homogenates of vessels from these animals showed that the activity of the NADH oxidase was doubled in concert with the increase in vascular ·O₂^- production. Endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 were abnormal in vessels from the angiotensin II–treated rats but were unaltered in the norepinephrine-treated rats. Finally, the endothelium-dependent vascular relaxations were restored toward normal by treatment of the vessels with a form of SOD (liposome-encapsulated SOD) that allows delivery of the SOD intracellularly. In summary, these studies demonstrated that hypertension caused by angiotensin II has a completely different effect on vascular ·O₂^- production and vascular reactivity from other forms of hypertension not associated with increased angiotensin II levels. In additional studies,¹⁸ we showed that even lower concentrations of angiotensin II, which had only minimal effects on blood pressure, also doubled NADH oxidase activity.

In these studies, we found that the angiotensin type-1 receptor antagonist losartan prevented the effect of angiotensin II and actually lowered vascular ·O₂^- production below the level observed in normal animals. These findings suggest that activation of the angiotensin type-1 receptor, even by the ambient levels of angiotensin II that are present in normal, physiological circumstances, may modulate vascular ·O₂^- production. Thus, it is conceivable that an ACE inhibitor could lower ·O₂^- rates of production even in situations in which angiotensin II is not elevated.

Activation of membrane oxidases and increases in vascular ·O₂^- production may have important roles in other conditions. Recently, we found that prolonged (3-day) nitroglycerin treatment is associated with an increase in rates of vascular ·O₂^- production and that this was at least partly responsible for the tolerance to nitroglycerin and cross-tolerance to endogenously released nitroglycerin.¹⁹

These new observations may provide insight into the mechanisms whereby both normal and elevated levels of angiotensin II can contribute to vascular disease. Increases in vascular ·O₂^- production may not only shorten the half-life of NO· but may contribute to oxidation of lipoproteins, damage to membrane lipids, and genesis of other radicals with a myriad of physiological and pathophysiological effects.²⁰ In contrast, measures that lower angiotensin II levels, such as treatment with an ACE inhibitor, may have beneficial effects on outcome by lowering vascular ·O₂^- production. This phenomenon may contribute to the beneficial effect of ACE inhibitors on outcome after myocardial infarction or in the setting of heart failure.²¹

In summary, there is mounting evidence that there are direct links between the renin/angiotensin system and the NO/L-arginine pathway in the endothelium and vessel wall. The underlying processes may involve modulation of NO· production, alterations of NO· degradation, or other, poorly understood phenomena. Of particular interest is the effect of angiotensin II on activation of membrane oxidases, leading to excessive degradation of NO· via ·O₂^-. Whatever the mechanism, the work of Mancini et al⁸ demonstrates the importance of this interaction and points to new mechanisms whereby ACE inhibitors and perhaps angiotensin II–receptor antagonists might benefit vascular function. Given that NO· may have a number of beneficial antiatherogenic effects, it will be important to determine whether ACE inhibitors can influence other properties of the endothelium and vascular smooth muscle.

	Selected Abbreviations and Acronyms

 

EDRF = endothelium-derived relaxing factor NO = nitric oxide PGH2 = prostaglandin H2 SOD = superoxide dismutase

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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