(Hypertension. 1999;34:958-963.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Protective Effects of Captopril Against Ischemic Stress
Role of Cellular Mg
From the Institute of Internal Medicine and Geriatrics (M.B., L.J.D.), University of Palermo, Italy, and the Division of Endocrinology, Metabolism and Hypertension (L.M.R.), Wayne State University, Detroit, Mich.
Correspondence to Prof Mario Barbagallo, MD, PhD, Associate Professor of Geriatrics, University of Palermo, Via F. Scaduto 6/c, 90144 Palermo, Italy. E-mail mabar{at}unipa.it
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Abstract |
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Abstract—Magnesium (Mg) deficiency enhances tissue sensitivity to ischemic damage, an effect reversed not only by Mg, but also by sulfhydryl (SH)-containing compounds. We therefore created an in vitro model of red blood cell ischemia to investigate whether the protective effects of these compounds might be related to effects on intracellular free Mg (Mgi) content. 31P-nuclear magnetic resonance (NMR) spectroscopy was used to measure the high-energy metabolites ATP and 2,3-diphosphoglycerate (DPG) and Mgi and inorganic phosphate (Pi) levels in erythrocytes before and for 6 hours after progressive oxygen depletion in the presence or absence of SH-compounds, including captopril, N-acetyl-L-cysteine (NAC), penicillamine, and N-(2-mercaptopropionyl)-glycine (MPG). Under basal aerobic conditions, captopril increased Mgi in a dose- and time-dependent fashion (174.5±5.3 to 217.1±5.1 µmol/L, P<0.05 at 100 µmol/L, 60 minutes). The SH compounds NAC, penicillamine, and MPG but not the non-SH compound enalaprilat also significantly raised Mgi in erythrocytes (P<0.05). With oxygen deprivation, a consistent decrease occurred in both ATP and 2,3-DPG levels associated with a rise in Pi and in the Pi/2,3-DPG ratio used as an index of high-energy metabolite depletion. Captopril, compared with control, retarded the rise in Pi and reduced the Pi/2,3-DPG ratio (P<0.008 and P<0.025 at 4 and 6 hours, respectively). Furthermore, the higher the initial Mgi and the greater the captopril-induced rise in Mgi, the greater the metabolite-protective effect (r=0.799 and r=0.823, respectively; P<0.01 for both). Altogether, the data suggest that Mg influences the cellular response to ischemia and that the ability of SH compounds such as captopril to ameliorate ischemic injury may at least in part be attributable to the ability of such compounds to increase cytosolic free Mg levels.
Key Words: captopril • ischemia • magnesium • red blood cells • sulfhydryls • spectroscopy, magnetic resonance
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Introduction |
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Captopril and various other reduced sulfhydryl (SH) group–containing compounds, unlike non-SH–containing converting enzyme inhibitors, have antioxidant properties.1 These properties include free radical scavenging2 3 and cardiovascular protective effects against ischemia and reperfusion injury,4 5 which have been presumed to depend on the presence of the reduced SH group. Certain evidence now suggests a relation of these SH-related effects to divalent cations such as Mg. First, Mg deficiency can directly cause coronary vasoconstriction,6 myocardial ischemia,7 and heart failure8 ; it also reduces tolerance to ischemic damage in heart and erythrocytes and to reperfusion injury.9 10 11 A distinct, long-term Mg-deficient cardiomyopathy has been defined that can be reversed both by treatment with Mg and by the addition of SH-containing angiotensin-converting enzyme (ACE) inhibitors such as captopril but not by enalaprilat or by other non-SH converting enzyme–inhibiting compounds.9 12 In all of these circumstances, the mechanism of this thiol group–related protective action of captopril, although presumed to be secondary to free radical scavenging and the subsequent decrease in reactive oxygen species, has yet to be defined.
Second, our group has recently reported that reduced glutathione (GSH), a physiological SH group–containing antioxidant, directly increases intracellular total and free Mg levels in erythrocytes.13 This was not true of oxidized glutathione, which is devoid of both a reduced SH group and any antioxidant activity. We wondered to what extent the protective effects against ischemic damage associated with other exogenous SH-containing compounds might be in part attributable to similar changes in cellular Mg content.
We therefore created a simple in vitro model of ischemic stress in human erythrocytes to investigate possible Mg-related mechanisms by which captopril and other SH-group compounds might exert their protective effects. We used 31P-nuclear magnetic resonance (NMR) spectroscopy to measure noninvasively intracellular free Mg (Mgi), the high-energy phosphorylated metabolites ATP and 2,3-diphosphoglycerate (DPG), and the accumulation of inorganic phosphate (Pi) in erythrocytes before and during 6 hours of progressive oxygen deprivation and metabolite depletion in the presence and absence of captopril, other ACE inhibitors, and other SH reagents. The present data suggest that SH reagent–induced changes in Mgi levels may help to explain, in part, the protective effect of these compounds against ischemic damage, aside from other antioxidant, free radical–related effects they may exhibit.
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Methods |
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Metabolite Depletion and Ischemic Stress Model
All volunteers gave informed consent in accordance with an institutional review committee–approved protocol at the Wayne State University Medical Center, Detroit, Mich. Twenty milliliters of heparinized blood was drawn between 9 AM and noon from unmedicated healthy volunteers (n=10;5 men, 6 women; mean age, 36.6±4.8 years; body mass index, 25.2±2.2 kg/m2) after they fasted overnight. Ten milliliters of the blood was processed by 31P-NMR techniques for analysis of the high-energy phosphate compounds 2,3-DPG and ATP. Basal measurements were taken, and then a stopper was placed atop the 12-mm NMR tube, thereby gradually decreasing the available oxygen and maximizing anaerobic fuel utilization; this incubation procedure was performed at 37°C in the presence and absence of 100 µmol/L captopril (the dose at which the maximum effect on Mgi was observed; see Results). Measurements were repeated at hourly intervals for the next 6 hours. Previous NMR measurements had demonstrated the stability of basal values under aerobic conditions for 6 hours.
31P-NMR Analysis of
Mgi
The other 10 mL of blood from each patient sample was processed
using 31P-NMR techniques to measure erythrocyte
Mgi levels before (basal, t=0 minutes)
and 30, 60, and 120 minutes after the addition of various compounds:
captopril (10 to 1000 µmol/L), enalaprilat (10 to 100
µmol/L), and other SH compounds,
N-acetyl-L-cysteine (NAC, 300
µmol/L), penicillamine (300 µmol/L), and
N-(2-mercaptopropionyl)-glycine (MPG, 300 µmol/L).
Doses of the other SH compounds tested were chosen to correspond to
slightly more than the maximally effective
Mgi-stimulating concentrations of captopril
tested (see Results). The concentration range chosen for testing the
effects of captopril was based on peak blood concentrations reported
after oral administration of 10- and 100-mg doses of this drug to
healthy male subjects.14
The method for 31P-NMR analysis of Mgi has been described in detail elsewhere.15 In brief, 10 mL of heparinized blood was spun at 2000 rpm for 10 minutes, and the plasma was discarded. The remaining packed cell fraction was decanted into a 12-mm NMR tube, and 31P-NMR spectra were recorded at 81 MHz at 37°C for 30 minutes on an XL200 spectrometer (Varian Associates Inc) in the Fourier transform mode with wide-band proton noise decoupling.
The Mgi concentration was determined
according to the following equation:
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=(ATP)free/(ATP)total,
as determined from the chemical shift differences of the 
- and
ß-phosphoryl group resonances of ATP in the
31P-NMR spectrum. Because the above calculation
is dependent on the steady-state equilibrium
Kd(MgATP) value, the lack of equilibrium
associated with the ongoing changes in ATP levels during progressive
oxygen depletion did not allow for a valid assessment of
Mgi during ischemia in this model. Hence,
the Mgi responses to all test substances reported
here were measured only under basal conditions.
31P-NMR Analysis of Erythrocyte
Metabolites
31P-NMR analysis was performed as
described above. In the erythrocyte, the main phosphoryl resonances
observed in the 31P-NMR spectra are,
sequentially, the 3- and 2-phosphate groups of 2,3-DPG and the 
-,
-, and ß-phosphate groups of ATP. In the metabolically
intact erythrocyte, no distinct resonance associated with
Pi is observed, because the low levels
present are obscured by the overlapping resonance of 2,3-DPG.
However, with metabolite depletion associated with progressive oxygen
depletion, a separate resonance peak associated with
Pi emerges (see Figure 1). Hence, elevations of this peak,
reciprocal decreases in the height and area of the 2,3-DPG and ATP
peaks, and the ratio of the Pi to 2,3-DPG
(Pi/2,3-DPG) peak heights were used as indexes of
metabolite depletion and cell ischemia.
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Statistical Analysis
Data for time-dependent changes in Mgi and
phosphorylated metabolite values before and after the
in vitro addition of different compounds were analyzed for
statistical significance using repeated measures ANOVA and subsequent
post hoc t test (Super-Anova, Abacus Concept). Pearson's
correlation coefficients were used to analyze the linear
correlations between variables. Differences were considered to be
statistically significant for P<0.05. All values are
expressed as mean±SEM.
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Results |
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With the onset of progressive oxygen depletion, which maximized anaerobic glucose use, a progressive fall in 2,3-DPG and ATP levels occurred over 4 to 6 hours, associated with the occurrence of and progressive rise in a distinct phosphoryl resonance peak due to Pi accumulation (Figures 1 and 2). These observations were quantitatively combined as the Pi/2,3-DPG ratio, which served as an index of metabolite depletion and failing cell viability. Under the same circumstances, incubation with captopril significantly retarded the rise in Pi compared with control and significantly reduced the Pi/2,3-DPG at 4 and 6 hours (Figure 2). Specifically, in control samples, Pi/2,3-DPG rose from 0.02±0.02 (t=0, basal) to 0.59±0.17 (t=4 hours), and to 1.39±0.33 at 6 hours of incubation. In contrast, in samples incubated with 100 µmol/L captopril, the rise in Pi/2,3-DPG was significantly blunted, from 0.02±0.02 (basal) to 0.40±0.10 (t=4 hours) to 0.93±0.20 (t=6 hours) (P<0.008 and P<0.025 at t=4 and 6 hours, respectively, versus controls; Figure 2).
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Under basal circumstances, captopril significantly elevated Mgi levels (Table; Figures 3a and 3b); enalaprilat did not. Specifically, captopril increased erythrocyte Mgi in a time- and dose-dependent fashion over the course of 120 minutes and at doses of 10 to 1000 µmol/L. These Mgi effects were maintained for 6 hours, the time during which progressive oxygen depletion was studied (see below). Peak Mgi effects were observed at 60 minutes and at a concentration of 100 µmol/L. At 60 minutes at different captopril doses, Mgi levels were 174.5±5.3 µmol/L (basal); 176.1±2.0 µmol/L (1 µmol/L captopril; P=NS); 200.1±4.4 µmol/L (10 µmol/L captopril; P<0.05); 217.1±5.1 µmol/L (100 µmol/L captopril; P<0.05); 208.0±4.7 µmol/L (300 µmol/L captopril; P<0.05); and 213±4.6 µmol/L (1000 µmol/L captopril; P<0.05) (Figure 1). In contrast, incubation with enalaprilat (10 to 100 µmol/L) for 60 minutes did not significantly alter Mgi content (Table).
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Mgi) responses to different
concentrations of captopril, measured 60 minutes after incubation (A),
and during 2 hours at a single captopril concentration (100
µmol/L) (B). * P<0.05 vs basal Mgi
levels.However, other SH compounds did raise Mgi in erythrocytes. When analyzed at 60 minutes, Mgi responses were as follows: for NAC (at 300 µmol/L), from 182.0±4.2 to 211.0±4.5 µmol/L, P<0.05; for penicillamine (at 300 µmol/L), from 171.5±9.1 to 198.0±7.8 µmol/L, P<0.05; and for MPG (at 300 µmol/L), from 179.0±5.2 to 196.8±7.2 µmol/L, P<0.05) (Table).
Altogether, a significant positive relationship was observed between the captopril-induced rise in Mgi levels and its protective effects on metabolite depletion: the greater the captopril-induced rise in Mgi, the greater the protective effect (r=0.823, P<0.01) (Figure 4). A further interaction between the Mgi status of the cell and the effect of captopril was noted when the captopril-induced change in Mgi was compared with basal Mgi levels. The higher the basal Mgi level, the greater the Mgi responsiveness (r=0.799, P<0.01), and, hence, the higher the basal Mgi, the greater the protective effect exerted by captopril (r=0.751, P<0.015).
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Discussion |
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Our group has focused on the role of altered cellular ion metabolism in mediating final common pathways of vascular diseases associated with hypertension, insulin resistance, diabetes mellitus, and aging.16 17 18 Current interest in the protective role of antioxidant compounds in cardiovascular disease recently led us to investigate the effects of the endogenous SH–containing antioxidant glutathione (reduced form, GSH) on Mg, in which reduced, but not oxidized glutathione stimulated Mgi content in human erythrocytes.13 In the present report, we used a simple in vitro model of ischemic stress in human erythrocytes to investigate the protective effects of exogenous SH compounds and the extent to which their protective effects could be linked to concomitant effects on Mgi levels.
With this red blood cell ischemic model, our present data show the following: (1) that both 2,3-DPG and ATP levels fall, whereas a separate Pi peak gradually emerges, and all of the above is reflected by the measurement of increased Pi/2,3-DPG over time; (2) that captopril and other SH compounds, such as NAC, penicillamine, and MPG all can enhance basal Mgi levels in erythrocytes, although the non-SH–containing enalaprilat cannot; (3) that captopril blunts ischemia-induced metabolite depletion, as indicated by the delayed rise in Pi, and Pi/2,3-DPG; and (4) that the protective effect of captopril on the above responses to ischemic stress was directly related to its effects on Mgi: the higher the captopril-induced rise in Mgi, the lower the Pi/2,3-DPG, and thus the greater the protective effect (Figure 4). Furthermore, (5) the cellular Mgi response to captopril is itself dependent on basal Mgi levels: the greater the Mgi, the more captopril increases Mgi and the more it protects against ischemic stress. Altogether, these data suggest (1) that oxygen deprivation of human erythrocytes in vitro provides a reasonable model system to test the protective effects of various agents against the metabolite depletion accompanying ischemic stress and (2) that the mechanism(s) by which SH compounds exert their protective effects may not be limited to the well-demonstrated actions of these compounds on free radical scavenging, but also may include their action to elevate Mgi levels.
Our present results are also consistent with previous observations in the literature that emphasize the significance of Mg deficits in cardiovascular ischemia. Increased oxygen free radical production, which may contribute to the pathophysiology of several human diseases,19 is associated with low intracellular Mg concentrations,20 and growing evidence links oxidative injury to Mg deficiency.21 22 Not only does Mg deficiency sensitize the myocardium to ischemic injury,9 but preexisting Mg deficiency is associated with myocardial free radicals such as ferrylmyoglobin23 and predisposes postischemic hearts to enhanced oxidative damage and functional loss,24 protection against which is afforded by various antioxidant compounds.21 More generally, chronic hypomagnesemia25 and conditions commonly associated with Mg deficiency, such as diabetes mellitus26 and aging,20 are all associated with an increase in free radical formation with subsequent damage to cellular processes. Indeed, Mg may itself possess antioxidant properties and scavenge oxygen radicals, possibly by affecting the rate of spontaneous dismutation of the superoxide ion.22 In dogs, it has been recently demonstrated that Mg infusions significantly attenuate the enhanced free radical formation after a 20-minute occlusion of the left anterior descending coronary artery followed by reperfusion.27
While both the carbonyl and thiol groups of captopril are essential for its activity as an ACE inhibitor, the antioxidant effects of captopril seem to depend on the SH moiety alone. Thus, SH compounds such as MPG, which exhibits no ACE-inhibiting activity, also protect hearts against myocardial ischemia and reperfusion in a concentration-dependent manner. Conversely, non-SH-containing ACE inhibitors such as enalaprilat are not protective.28 Similarly, SH-containing ACE inhibitors also protect endothelial cells in vitro against exogenously generated free radicals,3 and captopril, epicaptopril (a stereoisomer of captopril), and zofenopril all significantly protected male hamsters from cardiomyopathy due to Mg deficiency, whereas enalaprilat afforded only a slight (nonsignificant) protection.12 Captopril and zofenopril have also been found to attenuate postischemic contractile dysfunction of the viable but stunned myocardium during the early hours after relief from ischemia, whereas there is no consensus on the effects of other ACE inhibitors.29 In erythrocytes, captopril was protective against various oxidant stresses: hemolysis caused by 2,2'-azobis and hypochlorite, lipid peroxidation of erythrocyte membranes caused by tert-butyl-hydroperoxide (tBOOH) and hypochlorite, inactivation of erythrocyte membrane ATPases caused by tBOOH, and oxidation of hemoglobin caused by AAPH and tBOOH. Interestingly, increased membrane lipid peroxidation itself, as well as alterations of fatty acid composition and lipid-derived messengers, result from low-Mg environments.30 31 In all of these systems, the antioxidant effects observed have been related to the SH group; enalapril was either not protective or even increased the damage.32
Thus, although both Mg and SH compounds possess antioxidant properties, this is the first report in which a relation has been suggested between Mg itself and captopril-induced protection against metabolite depletion after ischemic stress. Although the mechanism of this Mgi-SH compound linkage remains undefined, it seems reasonable to suggest that the ability of endogenous glutathione to increase erythrocyte Mgi levels13 is being mimicked by the various exogenous SH–containing compounds tested here. Thus, GSH depends on an adequate supply of NADPH, which is normally derived from oxidative glucose metabolism in the erythrocyte through the pentose phosphate shunt pathway. Because the turnover of GSH is high, progressive oxygen deprivation would, by decreasing renewable NADPH stores, reduce endogenous GSH content. Furthermore, by placing an increased energy reliance on anaerobic glycolysis, ischemia makes the nonrenewable substrate availability in the test tube rate limiting, thereby increasing high-energy metabolite degradation. Under these conditions, exogenous SH compounds, by functioning as "substitute" GSH molecules, would provide the same direct antioxidant and Mgi-stimulating actions as would GSH itself, which would result in protection against the accelerated metabolite depletion, as we observed here.
Certain caveats that may limit the interpretation of the data should be considered. First, we did not perform complete dose-response curves for the noncaptopril compounds studied here. We thus cannot compare them with regard to their relative potency in stimulating Mgi levels in relation to the ability to protect against the ischemic changes induced in our model, which were not studied. Second, we did not measure cytosolic free calcium levels in this study, changes to which may mediate some of the cellular effects of magnesium deficiency, and which, consistent with studies in the literature,30 33 34 are directly regulated by both extracellular and intracellular Mg content. Third, although we believe certain insights may be gained from the use of this in vitro red blood cell–based ischemic stress model, the clinical relevance of our findings remain uncertain. Thus, these data clearly need to be substantiated and their implications tested in other model systems and ultimately in clinical disease states that involve direct insults to cardiac, brain, and/or peripheral vascular tissues.
These caveats notwithstanding, however, the present results demonstrate the direct in vitro actions of captopril to enhance Mgi content and to retard high-energy phosphate metabolite depletion after progressive oxygen deprivation, actions that appear to be related. Our data are thus consistent with a role of Mgi, at least in part, in the protective effect of captopril against ischemic injury. The utility of this simple model of red blood cell ischemic stress and further considerations concerning the mechanisms underlying this Mg ionic–antioxidant relationship will be the subject of future experiments.
Received May 10, 1999; first decision June 15, 1999; accepted July 9, 1999.
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