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Journal of Cardiovascular Magnetic Resonance, 3(3), 215–225 (2001) Preservation of Cardiac Function and
Energy Reserve by the Angiotensin-
Converting Enzyme Inhibitor Quinapril
During Postmyocardial Infarction
Remodeling in the Rat
Stephanie Hu¨gel, Michael Horn, Helga Remkes,Charlotte Dienesch, and Stefan Neubauer Department of Cardiology, Medizinische Universita¨tsklinik, Wu¨rzburg,Germany ABSTRACT
Purpose: Angiotensin-converting enzyme (ACE) inhibitors show beneficial long-
term hemodynamic effects in chronically infarcted hearts. The purpose of this study
was to test whether prevention of the deterioration of mechanical function by ACE
inhibitors is related to beneficial effects on high-energy phosphate metabolism that
is deranged in heart failure. Methods: Twelve-week old rats were randomly as-
signed to ligation of the left coronary artery [mycardial infarction (MI)] or sham
operation (Sham) and to the ACE inhibitor quinapril (ϩQ) (6 mg/kg/day per ga-
vage) or placebo treatment. Eight weeks later, cardiac function was measured in
the isolated heart by a left ventricular balloon (pressure-volume curves), and energy
metabolism of residual intact myocardium was analyzed in terms of total and isoen-
zyme creatine kinase activity (spectrophotometry), steady-state levels [adenosine
triptosphate (ATP), phosphocreatine], and turnover rates (creatine kinase reaction
velocity) of high-energy phosphates [31P nuclear magnetic resonance (NMR)] and
total creatine content [high-performance liquid chromatography (HPLC)]. Results:
Quinapril prevented post-MI hypertrophy and partially prevented left ventricular
contractile dysfunction [maximum left ventricular developed pressure 166 Ϯ 6, 83 Ϯ
16 (p Ͻ 0.05 MI vs. Sham), 139 Ϯ 13 mm Hg (p Ͻ 0.05 quinapril treated vs.
untreated) in Sham, MI and MIϩQ hearts]. Residual intact failing myocardium
showed a 17% decrease of MM-CK and a 16% decrease of mito-CK activity. Total
Address correspondence and reprint requests to Stephanie Hu¨gel.
Copyright  2001 by Marcel Dekker, Inc.
creatine was reduced by 23%, phosphocreatine by 26% and CK reaction velocity
by 30%. Parallel to improved function, treatment with quinapril largely prevented
the impairment of energy metabolism occuring post-MI. Conclusions: quinapril
treatment results in an improvement of high-energy phosphate metabolism, of energy
reserve via the creatine kinase reaction, and of contractile performance post-MI.
Key Words: ACE inhibitors; Creatine kinase; Remodeling; Myocardial infarction;
Energy metabolism
INTRODUCTION
left coronary artery was ligated after left thoracotomy un-der ether anesthesia. Sham operation was performed us- The prognosis of patients with heart failure remains ing an identical procedure except that the suture was poor, the most common cause of heart failure being post- passed under the coronary artery without ligation. Mor- myocardial infarction (MI) remodeling. Angiotensin- tality rate of infarcted rats for the first 24 h after the oper- converting enzyme (ACE) inhibitors are widely used to ation was 40–50%. All procedures conformed to the treat patients with post-MI left ventricular dysfunction Guide for the Care and Use of Laboratory Animals pub- (1,2). Clinical trials have shown that preventive treatment lished by the U.S. National Institutes of Health (NIH Pub- of heart failure patients with ACE inhibitors is cardiopro- tective and reduces morbidity and mortality (1). Hemody- After experiments were finished, left ventricles were namic improvements include decreased afterload, in- embedded in paraffin, and 20-µm sections were cut seri- creased coronary perfusion, and reduced left ventricular ally from apex to base of the heart. Sections were stained for collagen using Picrosirius Red staining. Slices were These clinical observations were predicted by animal digitized by using the NIH Image 1.59/ppc scanner soft- studies in rats with experimental MI, where the ACE in- ware (National Institutes of Health, Bethesda, USA) and hibitor captopril attenuated progressive ventricular dila- lengths of scar and noninfarcted muscle for both endocar- tation (4) and prevented LV and right ventricular (RV) dial and epicardial surfaces were determined for each sec- hypertrophy occurring in residual intact myocardium tion. Final infarct size was determined as the average of post-MI (5–8). The precise mechanisms by which ACE endo- and epicardial surfaces and is given as a percent- inhibition influences the remodeling process has not yet age. All hearts with an infarct size Ͻ30% were excluded been elucidated (7), but it has been attributed predomi- from the analysis (untreated n ϭ 12, and quinapril n ϭ 11).
nantly to their hemodynamic effects. However, the bio-chemical and molecular mechanisms whereby ACE in- Quinapril Treatment and Experimental
hibitors exert their beneficial action post-MI are just beginning to unfold. In a pilot study (9), we showed ear-lier that the ACE inhibitor quinapril preserved the phos- Before surgery rats were randomly assigned to one of the four groups: untreated sham (n ϭ 11), untreated MI In the present work, we studied the effects of quinapril (n ϭ 7), quinapril-treated sham (n ϭ 9) or quinapril- on LV dysfunction and dilatation post-MI by obtaining treated MI (n ϭ 7). Rats received 6 mg/kg/day of the pressure–volume curves and fully analyzing the metabo- ACE inhibitor quinapril orally (p.o.), initiated after re- lism of high-energy phosphates using 31P nuclear mag- covery from surgery. Quinapril was administered by ga- netic resonance (31P-NMR) spectroscopy, MR saturation vage daily at the same time of day. Quinapril treatment transfer, high-pressure liquid chromatography, and en- was discontinued 24 h before the hearts were isolated. A dosage of 6 mg/kg/day was chosen because in previousexperiments this dose decreased mean aortic blood pres-sure in vivo by 10% (data not shown) when therapy was initiated early (30 min after occlusion).
Animals, Myocardial Infarction,
and Determination of Infarct Size
Isolated Rat Heart Preparation
Infarcts or sham operations were performed in 12- Eight weeks after left coronary artery ligation or sham week-old Wistar rats. Left coronary artery ligation was operation, rats were anaesthetized by injecting 50 mg induced by a previously described technique (9–11). The pentobarbital sodium intraperitoneally. Hearts were iso- lated in a previously described technique (9,12). Retro- reference value for all resonances in the sequence of 31P grade perfusion of the heart was begun in the Langen- NMR spectra obtained for the protocol. Absolute ATP dorff mode at a constant temperature of 37°C and a concentrations were previously determined for sham constant coronary perfusion pressure of 100 mm Hg. For hearts as 10.8 Ϯ 0.8 mmol/L, for residual intact LV tissue control perfusion, phosphate-free Krebs-Henseleit buffer of MI hearts as 10.6 Ϯ 0.8 mmol/L by HPLC (14). Since was used as previously described (13). Coronary flow the protocol (histologic determination of LV infarct size, was continuously measured by an ultrasonic flow probe cutoff of the right ventricle for creatine analysis within (Transonic Systems Inc. Ithaca, NY) built into the perfu- 20 s) did not allow absolute ATP quantification by HPLC, ATP concentrations for sham and MI hearts wereassumed to be the same as for the previous study (14).
In addition, it was assumed that quinapril does not affect Cardiac Performance Measurements
normal ATP content, which is most likely the case: ATPcannot increase above normal levels, since mitochondrial All cardiac performance measurements were made us- ATP production is subject to close feedback inhibition ing standard procedures. A water-filled latex balloon was by ATP. ATP could not be determined by HPLC in this inserted into the left ventricle through an incision in the study, since left ventricles were fixed in formalin for in- left atrial appendage via the mitral valve, and secured by farct size measurements and right ventricles were cut off a ligature. The balloon was connected to a Statham and frozen, allowing determination of total creatine (Cr) P23Db pressure transducer (Gould Instruments, Glen and creatine (CK) kinase activity. ATP levels were not Burnie, MD) via a small-bore stainless-steel tube for con- determined in right ventricles because we cut off the right tinuous measurement of pressure and heart rate (HR) on ventricle from the beating heart and froze it after several a four-channel recorder (Graphtec Corp., Tokyo, Japan) seconds because freeze-clamping the beating heart was (9,12,13). Frank-Starling curves were obtained by in- impossible when we wanted to determine infarct size. In creasing the volume of the intraventricular balloon by our experience, ATP levels cannot reliably be determined 0.05 mL increments to raise the end-diastolic pressure when tissue is not directly freeze-clamped. Intracellular and to allow left ventricular developed pressure to reached a maximum (peak developed pressure).
i) was measured by comparing the chemical shift between inorganic phosphate and phosphocreatine withvalues obtained from a standard curve (15). The free cy- 31 P-NMR Spectroscopy
tosolic ADP concentration was calculated by using[ATP], [PCr], and [Hϩ] measured in the intact beating The perfused hearts were placed into a 20-mm NMR heart by 31P-NMR spectroscopy and total Cr measured sample tube and inserted into a probe seated in the bore chemically in RV homogenates, by assuming that CK is of a superconducting super-wide-bore (150 mm) 7.05- in equilibrium and by using a CK equilibrium constant Tesla magnet (Bruker, Rheinstetten, FRG), as previously described (14). Hearts were bathed in their own perfu- sate. An Aspect 3000 computer (Bruker, Rheinstetten, FRG) was used in the pulsed Fourier transform mode to The free energy change of ATP hydrolysis (∆G ) was cal- generate 31P-NMR spectra at 121.50 MHz. A 14-channel Shim unit served to homogenize the magnetic field. Sin-gle (‘‘one pulse’’) spectra were accumulated over 5-min ∆G(KJ/mol) ϭ ∆G° ϩ RT ln([ADP][Pi]/[ATP]) periods, averaging data from 152 free-induction decays where ∆G° (Ϫ30.5 KJ/mol) is the value of ∆G under obtained using a pulse time of 37.6 µs, a pulse angle of standard conditions of molarity, temperature, pH, and 45°, and an interpulse delay of 1.93 s. The resonance ar- [Mg2ϩ] (18), R is the gas constant (8.3 J/molK), and T eas corresponding to ATP, phosphocreatine, and inor- ganic phosphate (Pi), which are proportional to the num-ber of phosphorus atoms of the respective compound,were measured by integration using the NMR1 software 31 P-NMR Magnetization Transfer
(TRIPOS, Munich, Germany) and were corrected for par- Measurements of Creatine Kinase Kinetics
tial saturation. In each heart, the area of the [γ-P]ATPresonance of the first spectrum obtained under control For magnetization transfer experiments, each broad- conditions was arbitrarily set to 100% and used as the band pulse was preceded by a low-power, narrowband pulse at the resonance frequency of [γ-P]ATP for 0, 0.3, (28), and lactate dehydrogenase (29) enzyme activities 0.6, 1.2, 2.4, or 3.6 s as previously described (14,19). For were measured using an Ultraspec III spectrophotometer each of the 6 saturation transfer spectra, 64 scans were (Pharmacia Biosystems, Freiburg, FRG). To measure the accumulated by repetitively cycling through the six dif- CK isoenzyme distribution, the Rapid Electrophoresis ferent times of presaturation. A complete saturation trans- System (REP, Helena Diagnostika GmbH) as separation fer experiment was acquired in 32 min. Stability of the unit and the REP CK Isoforms Kit (Helena Diagnostika preparation was assessed by comparing one-pulse spectra GmbH) for agarose gel and incubation solution were obtained before and after each magnetization transfer ex- used. The Electrophoresis Data Center (EDC, Helena Di- periment. Magnetization transfer measurements of the agnostika GmbH) automatically quantified the separated Experimental Protocols
were analyzed according to the two-site chemical ex-change model of Forsen and Hoffman (20), providing es- All hearts were given 10–15 min for stabilization timates of the pseudo-first-order rate constant (kfor) and where LV end-diastolic pressure was set to 10 mm Hg by the intrinsic longitudinal relaxation time for PCr (T1).
adjusting the balloon volume in the left ventricle. After Multiplying the rate constant by substrate concentration ‘‘baseline’’ left ventricular pressures (mm Hg), heart rate (minϪ1), and coronary flow (ml/min) were recorded, theballoon was emptied. A LV pressure–volume curve was Biochemical Measurements
performed. Recordings of all parameters were made ateach step when a new steady state was reached, which Since biochemical measurements cannot be made in occurred within 2 min. After another 15 min of stabiliza- formalin-pretreated hearts (necessary for histologic de- tion (end-diastolic pressure set to 10 mm Hg), a 5-min termination of infarct size), right ventricles were sepa- one-pulse spectrum was recorded. Thereafter, a set of six31 rated after the NMR-experiment and frozen in liquid ni- P-NMR magnetization transfer spectra was recorded in trogen. We have previously shown that changes of total 32 min. After obtaining a final one-pulse 31P-NMR-spec- creatine and creatine kinase isoenzyme activities in trum, the right ventricle was separated and rapidly frozen chronically infarcted hearts are mostly similar for left and in liquid nitrogen for HPLC and enzyme measurements and the left ventricle was fixed in formalin for determina-tion of infarct size.
High-Pressure Liquid Chromatography
Measurements
Statistical Analysis
A piece of tissue (ϳ10 mg) was separated with a Min- All data are presented as mean ϮS.E.M. Results of imot 40/|E drill (Proxxon GmbH, Niersbach, Germany) quinapril-treated and untreated sham and MI hearts were under liquid nitrogen and was analyzed for total creatine compared by multicomparison analysis of variance content as previously described (23,24). Free Cr was then (ANOVA) (30). Calculations were performed by a com- calculated for each heart as total Cr minus PCr. Noncolla- mercially available program, Stat View SEϩGraphics gen protein was measured by the method of Lowry et al.
(Brainpower Inc., Calabasas, CA, USA). A p-value of (25). Metabolite concentrations were expressed as mmol/ less than 0.05 was considered significant.
L, assuming that 50% of wet weight represents intracellu-lar H2O (26).
Heart Weight, Body Weight, and Infarct
Enzyme Analysis
From each sample, 5–10 mg of tissue were homoge- Table 1 shows infarct size, body weight, heart weight, nized as previously described (22). Before the addition LV weight, RV weight, and their ratios for the four stud- of Triton, aliquods for measurements of protein and Cr ied groups of rats. Infarct size was comparable for the content were taken. Creatine kinase (27), citrate synthase two infarcted groups. Body weight was significantly re- Table 1
LV ϭ left ventricular; RV ϭ right ventricular.
* p ϭ 0.05 sham vs. MI.
† p Ͻ 0.05 quinapril-treated vs. untreated.
duced in quinapril-treated infarcted rats. Heart weight Figure 1 shows LV developed pressure to LV volume and LV weight were substantially increased in the in- relations for the four groups. The curve for the infarcted farcted untreated group. Quinapril treatment prevented untreated group was shifted to the right with a signifi- these increases. Similar effects were observed for their cantly reduced maximal developed pressure compared to ratios. RV weight in absolute and relative terms was not the sham-operated untreated group (Table 2). The shift of the curves was partially prevented by quinapril treat-ment, the reduction of the maximum developed LV pres- Cardiac Performance
sure in infarcted hearts was prevented by quinapril. Onaverage, heart rate was 273 Ϯ 4 beats/min and was not Table 2 shows HR, coronary flow, and left ventricular significantly different among groups. Coronary flow was developed pressure (LVDP) for the four experimental 22.7 Ϯ 0.6 mL/min on average and was not significantly groups, all recorded at an end-diastolic pressure set to 10 mm Hg. LV developed pressure was significantly re-duced in untreated, infarcted hearts (62 Ϯ 11 vs. 130 Ϯ High-Energy Phosphate Metabolism
4 mm Hg in sham). Although treatment did not affect leftventricular–developed pressure in sham-operated hearts, Representative 31P-NMR spectra obtained from sham- quinapril treatment prevented the decrease in LV devel- operated and infarcted hearts, untreated and quinapril- oped pressure in infarcted hearts (110 Ϯ 8 in quinapril- treated, are shown in Figure 2. Mean values for high- and treated vs. 62 Ϯ 11 mm Hg in untreated infarcted hearts).
low-energy phosphates and pHi are shown in Table 3.
Table 2
Cardiac Performance and Coronary Flow for All Experimental Groups HR ϭ heart rate; CF ϭ coronary flow; LVDP ϭ left ventricular developed pressure; LVDP LVDP.
* p Ͻ 0.05 sham vs. MI.
† p Ͻ 0.05 quinapril-treated vs. untreated.
Figure 1.
LV developed pressure to volume relations for the four groups studied. There is a rightward and downward shift in the untreated infarcted hearts, which was partially prevented by quinapril treatment.
Inorganic phosphate resonances were not significantly infarcted, treated and untreated, hearts. The total Cr pool different among groups. The reduction of PCr concentra- was significantly reduced in untreated infarcted hearts.
tion in infarcted hearts was prevented by quinapril treat- Treatment with quinapril prevented this reduction.
ment. The calculated mean values for free cytosolic ADPconcentrations were 106 Ϯ 7 µM and for the free energy Creatine Kinase Reaction Velocity
change of ATP hydrolysis were Ϫ57.8 Ϯ 0.2 J/mol, re-spectively. There were no differences among groups (Ta- Data from saturation transfer experiments are also ble 3). As also shown in Tab. 3, intracellular pH was shown in Table 3. On average, the T1 of PCr was 3.16 Ϯ 7.16 Ϯ 0.01 and values were comparable for sham and 0.17 s and was similar for all groups. Both the rate and Figure 2.
Representative 31P-NMR spectra for the four groups studied. A reduction of PCr in the untreated infarcted heart and the preservation of PCr in the quinapril-treated infarcted heart is visible.
Table 3
High-Energy Phosphate Metabolism for All Experimental Groups * p Ͻ 0.05 sham vs. MI.
† p Ͻ 0.05 quinapril-treated vs. untreated.
‡ Taken from previous study (20).
the extent of saturation transfer from PCr to [γ-P]ATP Biochemical Analysis
were decreased in untreated infarcted hearts. Thepseudo–first-order unidirectional rate constant for un- Table 4 summarizes the results of enzymatic analysis treated infarcted hearts decreased significantly from of right ventricles frozen after the experiment. Total CK 0.96 Ϯ 0.04/s to 0.75 Ϯ 0.05/s. Quinapril prevented this activity was 8.4 Ϯ 0.3 IU/mg protein and was not differ- decrease. As shown in Figure 3, Cr reaction velocity was ent among groups. CK isoenzyme distribution showed an reduced in untreated infarcted hearts by 30%. This de- increase of the fetal BB and MB isoenzymes, whereas crease was completely prevented by quinapril treatment.
the mitochondrial CK isoenzyme showed a trend for adecrease. Treatment with quinapril prevented the in-crease of the fetal CK isoenzymes after myocardial in-farction. There was no difference in the reduction of MMisoenzyme in sham-operated and infarcted, untreated andtreated hearts (Tab. 4). Lactate dehydrogenase activity,a glycolytic enzyme, was 1.1 Ϯ 0.0 mIU/mg protein andcitrate synthase activity, a marker for mitochondrialmass, was 0.9 Ϯ 0.0 IU/mg protein, and these enzymeactivations were not significantly different betweengroups.
DISCUSSION
Definition of the Model
In this study, we employ the clinically most relevant model of chronic heart failure, the rat heart postmyocar-dial infarction. In untreated infarcted hearts, changes in Figure 3.
Mean values for creatine kinase reaction velocity (CK flux) for the four groups studied, demonstrating a substan- cardiac structure and function were as previously de- tial reduction of CK reaction velocity in the untreated group scribed (14,22,31): Impaired contractile performance was post-MI. Quinapril treatment prevented this reduction. * ϭ p Ͻ accompanied by structural dilatation, indicated by a 0.05 sham vs. MI; † ϭ p Ͻ 0.05 quinapril-treated vs. untreated.
rightward and downward shift of the pressure–volume Table 4
Enzyme Activities in Right Ventricle of All Experimental Groups Total creatine kinase (Total CK activity; IU/mg protein); MM-, mito-, MB- and BB-CK isoenzymes (absoluteactivity in IU/mg protein and percentage of total creatine kinase activity); LDH (lactate dehydrogenase; IU/mgprotein) and citate synthase (IU/mg protein).
* p Ͻ 0.05 sham vs. MI.
† p Ͻ 0.05 quinapril-treated vs. untreated.
relation with a reduced maximum LV developed pres- enalapril to severely failing cardiomyopathic hamsters improved survival and hemodynamic performance. The Untreated infarcted hearts also showed impairment of present study shows that quinapril treatment prevented energy metabolism characteristic of failing myocardium: the decrease of LV developed pressure occurring post- Reduction of total and phosphorylated Cr levels (14,32– MI, whereas quinapril had no effect on LV developed 34), while steady state ATP levels were unaltered (14).
pressure in hearts of sham-operated animals. As assessed Based on CK equilibrium assumptions, this also indicates by Frank-Starling curves, ACE inhibition with quinapril unchanged free ADP and ∆G levels. However, metabolic counteracted dilatation and preserved LV function in the data presented in this study show ‘‘baseline’’ perfor- MI model, an effect that has also been observed in vivo mance conditions only. The rate of phosphoryl transfer (6). Part of the effect may be explained by alterations in (Vfor) measured as CK reaction velocity was reduced by 30%. A reduction of energy reserve via the creatine ki- In the isolated isovolumic heart preparations used in nase reaction as indicated by decreased PCr and CK reac- this study, coronary flow was not significantly changed tion velocity may contribute to the development of con- in hearts from quinapril-treated animals. Our data indi- tractile failure (35). The alterations of CK isoenzyme cate that global coronary perfusion was not significantly distribution were as previously described (14,22) and altered by chronic MI or ACE inhibition. Therefore, the showed increased MB-CK and BB-CK activity. The beneficial effects of chronic ACE inhibitor treatment on heart failure model used here is well suited to study the function and energy metabolism are unlikely to be related chronic effects of both protective (6,9,36) and deleterious to effects on improved global perfusion and microcircula- tion after MI. However, the isolated buffer-perfused ratheart model is not an appropriate model to study flowchanges, since coronary flow is ten times higher than it Effects of Quinapril on Cardiac Geometry
is in vivo under conditions of blood perfusion.
and Function Postmyocardial Infarction
In clinical heart failure studies (1,6), ACE inhibitors Effects of Quinapril Treatment on Cardiac
have been shown to chronically decrease mortality, re- Energy Metabolism
duce LV hypertrophy, and improve LV function. How-ever, the exact mechanisms underlying these beneficial Energy metabolism is compromised in heart failure effects remain to be determined. For example, Nascim- (35), and one hypothesis is that ACE inhibitors like quin- ben et al. (38) showed that supplying the ACE inhibitor april may, at least in part, exert their beneficial effects on cardiac function by maintaining normal energy metab- function and metabolism can be abolished by chronic olism. In the present study, we demonstrate that the func- bradykinin receptor blockade (46). On the other hand, tional effects of quinapril are accompanied by beneficial Yamaguchi et al. (47) reported an attenuation of the re- effects on cardiac energy metabolism: PCr content, CK duction in ryanodine receptor density in the viable left reaction velocity, and total Cr content were all main- ventricle of the infarcted rat with CHF and an attenuation tained at normal levels, and the fetal reprogramming of of the sarcoplasmic reticulum dysfunction which is in CK isoenzymes was prevented. Maintaining energy re- part attributed to prevention of downregulating of the serve via CK at normal levels, ACE inhibitors may, among multifaceted other biochemical mechanisms ofthe compounds, exert their beneficial effects.
Study Limitations
Only a few investigators have previously studied the effects of ACE inhibition on cardiac energy metabolism.
Because our study design required that the animals Sanbe et al. (40) showed that energy metabolism and mi- were killed at 2 months, we could not quantitatively tochondrial oxidative function was improved by treat- assess differences in survival rates due to treatment. En- ment with various ACE inhibitors postmyocardial in- zyme and HPLC analyses were performed in intact resid- farction. Using a different model of heart failure, ual RV tissue, because the left ventricle was formalin- Nascimben et al. (38) showed that, in Syrian cardiomyo- pretreated for histologic determination of infarct size.
pathic hamsters, decreased flux through the CK reaction However, we previously showed (22) that changes in en- leads to decreased capacity for ATP synthesis and may ergy metabolism are mostly similar for the left and right contribute to reduced contractile performance. Here, ventricles. Another limitation of the present study is that enalapril treatment resulted in increased phosphoryl only a single dose of quinapril, one that showed a mild transfer through the CK reaction in failing myocardium, hemodynamic effect, was tested. Thus, a dose-depen- and this increase was coupled to improved cardiac perfor- dence of quinapril’s effects on energy metabolism also mance. It is particularly interesting that, in Nascimben’s study (38), the increase of CK reaction velocity wasmainly due to an increase of the first-order rate constantK, while in our study both K and substrate concentration ACKNOWLEDGMENTS
(PCr) were increased. This suggests that ACE inhibitorsdo not simply maintain PCr and total Cr levels but, in This work was supported by a research grant from addition, have effects on the kinetic properties of the en- Go¨decke, Park Davis, Freiburg, Germany and by the Deutsche Forschungsgemeinschaft, SFB 355, Teilprojekt The mechanisms whereby ACE inhibitors maintain phosphocreatine and total Cr at normal levels remain tobe determined. However, since total Cr levels seem to be REFERENCES
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