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Circulation. 1997;95:14-16

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(Circulation. 1997;95:14-16.)
© 1997 American Heart Association, Inc.

Articles

Modulation of Myocardial Oxygen Consumption Through ACE Inhibitors

NO Effect?

Jørn Bech Laursen, MD; David G. Harrison, MD

the Department of Medicine, Emory University School of Medicine (J.B.L., D.G.H.), Atlanta, Ga; the Atlanta Veterans Administration Medical Center (D.G.H.), Atlanta, Ga; and Medical Department B, Division of Cardiology (J.B.L.), Rigshospitalet, Denmark.

Correspondence to David G. Harrison, Professor of Medicine, Cardiology Division, Emory University School of Medicine, Atlanta, GA 30322.


Key Words: Editorials • endothelium-derived factors • angiotensin


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
In this issue of Circulation,1 Zhang and coworkers provide convincing evidence that ACE inhibitors reduce myocardial oxygen consumption by preventing the degradation of bradykinin, which subsequently stimulates the release of nitric oxide (NO). They propose that NO inhibits mitochondrial respiration, thus reducing myocyte oxygen use. This is an exciting observation because it provides a new mechanism whereby ACE inhibitors might benefit ischemia beyond simply inhibiting the formation of angiotensin II, thus reducing the vasoconstrictor effect of this octapeptide. These results are further evidence for a role of bradykinin in the response of tissues to ACE inhibitors. The mechanism enabling these interactions to occur is coming to light on the basis of studies such as the current one from Zhang et al.

Interest in bradykinin and related kinins as cardiovascular mediators has grown tremendously in the past several years, largely because it has been recognized that they potently stimulate release of NO and prostacyclin from endothelial cells. Bradykinin and Lys-bradykinin, respectively, are formed when one of a family of enzymes, known as kallikreins, act on either heavy- or low-molecular-weight kininogens.2 This action involves cleavage of amino acids from both the C- and N-terminal ends of the kininogen peptides and takes place both in plasma (for heavy-molecular-weight kininogen) and tissues (for low-molecular-weight kininogen). The kininogens were previously thought to be expressed primarily by hepatocytes; however, it is now clear that many tissues, including vascular cells3 4 and the heart,5 also express kininogens. The kallikreins as well are made by many cell types and are produced by vascular cells in a continuous fashion.6 Thus, many tissues, including the heart and vascular cells, have an intact kallikrein/kininogen system capable of producing bradykinin. The mechanisms whereby bradykinin production is regulated remain unclear; however, there is some evidence that flow might increase bradykinin production from the endothelium and that this may be responsible for flow-mediated vasodilation.7

Perhaps equally critical as how bradykinin is made in the vessel wall is the manner in which it is degraded. The principal enzyme involved in this process, initially identified in 1967, is kininase II.8 As early as 1970, it was found that this enzyme is identical to the angiotensin I–converting enzyme.9 Soon thereafter, it was proposed that a portion of the effects of the ACE inhibitors might occur by prolonging the half-life of endogenously produced bradykinin.10 In the 1980s, attention was turned to the possible role of other mediators in the response to bradykinin. For example, it was shown in the late 1970s that captopril stimulated the release of prostaglandin-like substances from perfused lungs.11 In 1986, it was shown that ramipril could stimulate prostacyclin synthesis in rat aorta.12 The mechanisms by which this occurred were made more clear in 1991 when Busse and Lamontagne13 showed that ACE inhibitors could increase intracellular calcium levels in cultured endothelial cells and that this effect was enhanced by addition of bradykinin and blocked by the bradykinin antagonist HOE 140. Because intracellular calcium is the major stimulus for activation of the NO synthase enzyme, it followed that ACE inhibitors might stimulate NO production. Indeed, in a related study, Hecker et al14 showed that cGMP levels in cultured endothelial cells were increased by ACE inhibition and that this effect could be blocked by NO synthase inhibition. That study rather convincingly demonstrated that ACE inhibitors could enhance the release of NO by increasing intracellular calcium through a bradykinin-dependent mechanism. Despite the attractive aspects of this concept, the evidence supporting a role of bradykinin in vivo in the response to ACE inhibitors has been controversial. There are two facets of this controversy that are worthy of consideration.

The first aspect of this issue is whether or not there is sufficient bradykinin present during normal conditions (either in the vessel wall, the myocardium, or plasma) to allow this effect to occur. Bradykinin is degraded within 15 seconds in plasma, and an estimated 65% to 90% of the bradykinin is destroyed during one pass through the pulmonary circuit.15 The normal plasma levels of bradykinin are 10 to 50 pg/mL, well below the threshold (>100 pg/mL) for a hypotensive effect. In several studies, plasma levels of bradykinin do not change significantly during administration of ACE inhibitors.15 16 Important to these considerations, however, is that local levels of bradykinin in the vessel wall are likely increased by ACE inhibitors. For example, Baumgarten et al17 showed that after administration of ramiprilat to isolated hearts, the levels of bradykinin in the coronary effluent increased dramatically. Nevertheless, it is not always possible to detect a physiological (as opposed to a biochemical) effect of ACE inhibitors that would be mediated by NO. For example, ACE inhibitors will augment relaxations caused by exogenously administered bradykinin but do not themselves produce vasorelaxation in the absence of added bradykinin.18

The second concern regarding the relevance of this effect of ACE inhibitors on the kinin system is that the biological effect of preventing formation of angiotensin II is so great as to overwhelm any additional effect of prolonging the half-life of bradykinin. In this regard, it has been difficult to demonstrate any obvious differences between ACE inhibition and angiotensin II receptor blockade on lowering of blood pressure, leading some to suggest that this additional bradykinin-dependent role of ACE inhibitors may not be important. Considering studies such as the present one by Zhang et al,1 one might conclude that it may be necessary to look beyond the blood pressure–lowering effects of ACE inhibitors to understand the additional beneficial effects of these drugs as they are related to the bradykinin/NO system. Nevertheless, as discussed below, studies are needed to define the clinical relevance of this additional effect of ACE inhibitors.

It has become possible to tease out the various roles for bradykinin, NO, and the angiotensin II receptor in the response to ACE inhibitors because in the last few years, relatively specific inhibitors for each of these have become available. Using inhibitors such as these, Hartman19 showed that infarct size in the rabbit could be reduced by the ACE inhibitor ramiprilat and was not affected by losartan (the specific antagonist of the angiotensin II AT1 subtype receptor). The effect of ramiprilat was negated by HOE 140 and by NO synthase inhibition.19 Similarly, Farhy et al20 showed that ACE inhibitors prevented neointimal formation to a greater extent than losartan after balloon injury of the carotid artery in rats. If rats were treated with either N{omega}-nitro-L-arginine methyl ester (to block NO synthase) or HOE 140, the effect of the ACE inhibitor was reduced and was equivalent to that of losartan. Those authors suggested that a large portion of the effect of the ACE inhibitors likely occurred via the kallikrein/bradykinin/NO pathway.

In the present study by Zhang and coworkers,1 a similar experimental paradigm was used to examine the effect of ACE inhibitors on myocardial oxygen consumption. There are several unique aspects of the study. First, the authors were able to demonstrate directly that the various ACE inhibitors could stimulate production of nitrite (a stable degradation product of NO). This was prevented by HOE 140, proving a role for bradykinin as an intermediate in this process. Using an oxygen electrode, the authors were able to show that this effect of the ACE inhibitors was associated with a dose-dependent decrease in myocardial oxygen consumption in slices of cardiac muscle. This finding builds on earlier studies showing that NO can modulate oxygen consumption in isolated hindlimb preparations, isolated skeletal muscles, and the entire body. Zhang et al1 have shown that this can occur via an interaction between vascular endothelial cells and adjacent parenchymal cells. In the present study of heart tissue, it is likely that the NO involved was derived from microvessels in the tissue. It should be noted that myocardial myocytes also contain NO synthase and express bradykinin B2 receptors, which could also be involved in this response.

A potential criticism of this study is that the authors did not examine the effect of losartan on either nitrite production or myocardial oxygen consumption. Vascular and cardiac cells are capable of producing angiotensin II,21 and it is conceivable that the loss of endogenously produced angiotensin II may have mediated some of the effects caused by the ACE inhibitors. If this were the case, one might predict that losartan would mimic the effect of ACE inhibition. The fact that HOE 140 prevented the increase in nitrite production by microvessels and the decrease in oxygen consumption by heart slices suggests that the effect of the ACE inhibitors was not dependent on the loss of angiotensin II.

How does NO, released in response to ACE inhibitors, inhibit myocardial respiration? This knowledge was initially derived from studies of activated macrophages in which NO synthase was induced. This inducible NO synthase makes large quantities of NO, which seems to be involved in the killing of target cells such as parasites, tumor cells, and bacteria. For the most part, this occurs via the formation of very reactive metabolites of NO (species such as peroxynitrite, nitrosonium anions, and N2O3), which react with iron-sulfur centers in the mitochondrial electron transport chain. NO itself does not participate in the formation of such nitroso-iron sulfur complexes but has been shown to bind to cytochrome oxidase in nanomolar concentrations in a reversible fashion.22 Cytochrome oxidase is therefore a likely target for regulation of oxygen consumption by NO. The precise mechanism by which this occurs remains unknown.

The current results may explain in part some of the beneficial effects observed with ACE inhibitors in the treatment of patients with ischemic heart disease. The findings raise the question of whether or not ACE inhibitors might diminish myocardial oxygen demand and thus have antianginal effects in the manner of ß-adrenergic antagonists. There have been several studies in patients with congestive heart failure and at least one study of patients with hypertension showing that ACE inhibitors prolong treadmill exercise time. These results are not surprising, given the beneficial effects these drugs have on systemic hemodynamics and ventricular afterload. The effect of ACE inhibitors on treatment of angina in normotensive patients without heart failure has only been examined in a relatively few patients with mixed results.23 24

One interpretation of studies such as the present one by Zhang and coworkers is that ACE inhibitors may be highly preferable to angiotensin II receptor antagonists in cardiovascular therapy. Such a conclusion is probably premature. First, these effects are dependent on an intact NO system. Many of the diseases in which ACE inhibitors are used, including hypercholesterolemia, atherosclerosis, heart failure, hypertension, and diabetes, are associated with abnormalities of NO production and/or effect.25 In these states, NO is either not produced appropriately or is inactivated by reactive oxygen species such as superoxide. It is therefore conceivable that individuals with these common disease processes in whom the NO system is dysfunctional might not benefit from this NO-mediated effect of ACE inhibitors. Second, there are clear-cut effects of angiotensin II in the cardiovascular system that lead to untoward consequences such as excessive vasoconstriction, activation of endothelin transcription, stimulation of myocardial and vascular smooth muscle hypertrophy, and activation of vascular superoxide production.26 27 It is now recognized that there are alternate pathways for angiotensin II formation (for example, via chymase28 ) not affected by ACE inhibitors. It is therefore conceivable that treatment strategies in the future may involve a two-pronged approach, using both angiotensin II receptor antagonists to prevent the effects of angiotensin II on vascular and myocardial tissues and ACE inhibitors to achieve the bradykinin/NO–mediated effect demonstrated by Zhang et al.1 The clinical significance of this alternate effect of ACE inhibition, however, needs to be defined before such treatment strategies are undertaken.


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


*    References
up arrowTop
 up arrowIntroduction
 *References
 

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