(Hypertension. 1999;34:291-295.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Late Treatment With Ramipril Increases Survival in Old Spontaneously Hypertensive Rats
From Hoechst Marion Roussel, DG Cardiovascular Diseases, (W.L., P.W., B.A.S., R.H.A.B., G.W.), Frankfurt/Main, Germany and the Department of Chemistry, Center for Biomedical Research, (T.M.), Oakland University, Rochester, Mich.
Correspondence to Wolfgang Linz, PhD, Hoechst Marion Roussel, DG Cardiovascular Research (H813), D-65926 Frankfurt/Main, Germany. E-mail wolfgang.linz{at}hmrag.com
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Abstract |
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Abstract—Spontaneously hypertensive rats (SHR) begin to die from cardiovascular complications at
15 months of age. We
tested whether chronic ACE-inhibitor treatment would extend
the lifespan of such old animals. We also studied cardiac
hypertrophy and function, endothelial
function and expression, and activity of NO synthase (eNOS). One
hundred 15-month-old SHR were randomized into 3 groups, control (n=10),
placebo-treated (n=45), and ramipril-treated with an antihypertensive
dose of 1 mg · kg-1 · d-1 in
drinking water (n=45). Ex vivo experiments were performed after 15
months (control) and 21 months, when 80% of the placebo group had
died. Late treatment with ramipril significantly extended lifespan of
the animals from 21 to 30 months. Fully established cardiac
hypertrophy, observed in placebo-treated animals and in
controls, was significantly reversed by ramipril treatment. In isolated
working hearts, a significantly improved function associated with
increased cardiac eNOS expression was seen versus placebo and control
hearts. Endothelial dysfunction in isolated aortic
rings from control and placebo-treated SHR was significantly improved
by ACE inhibition and associated with enhanced NO release. Late
treatment of SHR with the ACE inhibitor ramipril extended
lifespan from 21 to 30 months, which is comparable to the lifespan of
untreated normotensive Wistar-Kyoto rats. This lifespan extension,
probably due to blood pressure reduction, correlated with increased
eNOS expression and activity followed by a regression of left
ventricular hypertrophy and cardiac and
vascular dysfunction.
Key Words: ramipril • cardiac function • hypertrophy • endothelium • rats, inbred SHR • nitric-oxide synthase, endothelial
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The spontaneously hypertensive rat (SHR) is an animal model of nature. It develops high blood pressure (BP) that has similarities to essential hypertension in humans.1 SHR die from cardiovascular complications at an age of about 15 months after a long period of stable, compensated cardiac and arterial hypertrophy as a result of persistent hypertension. The cardiovascular complications mainly involve ventricular fibrillations resulting from multiple microinfarctions and heart failure.2 3
Some data obtained in genetically hypertensive rats point to a prolongation of survival through angiotensin-converting enzyme (ACE) inhibition. Short-term antihypertensive treatment of SHR between 6 and 10 weeks of age with the ACE inhibitor perindopril appeared to extend their lifespan.4 In an earlier study, male SHR were treated with captopril from the ages of 12, 18, or 21 months until 24 months. The degree to which captopril prevented myocardial dysfunction appeared to be related to the age at which captopril treatment was initiated and the duration of captopril administration.3
Recently, we showed that lifelong ACE inhibition with ramipril doubles life expectancy in stroke-prone SHR, which matches the life expectancy of normotensive Wistar-Kyoto rats (WKY).5 This effect correlated with the prevention of the development of hypertension, of cardiac left ventricular hypertrophy most likely associated with improvement of myocardial function, and with the preservation of endothelial function. The latter was accompanied by enhanced upregulation of endothelial NO synthase (eNOS) expression and activity.5 6 Inspired by the outcome of this prevention study, the present study investigated whether late treatment of SHR with the ACE inhibitor ramipril is able to reverse fully developed cardiac hypertrophy and endothelial dysfunction, and, thus, improve survival.
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Methods |
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Housing and Animal Care
Male SHR were purchased from Møllegaard, Denmark, and housed 3 per cage under standardized conditions of temperature, humidity, and light. The rats had free access to standard diet (Altromin Maintenance Diet 1320, sodium content 0.2%) and drinking water. All experiments were performed in accordance with the German animal protection law.
Study Design
The present study was comprised of 100 animals, aged 15
months, randomly assigned to 3 groups. Two groups had 45 animals each,
and 1 group had 10 animals. The latter group served as controls at the
start of the study and was used as described in the interim
analysis. The other rats were treated by drinking water that
contained either placebo or an antihypertensive dose of ramipril (1
mg · kg-1 ·
d-1). The treatment commenced immediately after
randomization and was adjusted to the actual water consumption. Body
weights and systolic BP were determined every 3 months, by use
of tail plethysmography. Deaths were recorded as they occurred.
Interim Analysis
The interim analysis was scheduled for the time when
80% of the placebo-treated animals had died, which was after 21
months. Ten animals from each group were randomly selected and
anesthetized (hexobarbitone, 80 mg/kg IP). Blood samples were drawn,
and thoracic aortas and hearts were removed for molecular, biochemical,
and/or functional analyses. Renin activity, and concentrations
of aldosterone and angiotensin (Ang) I and
II were determined in plasma.5 ACE activities in
plasma, thoracic aortas, and right cardiac ventricles were
radioenzymatically measured by use of 3H-Gly-Gly
as substrate (Hycor ACE-activity test).
Isolated Working Heart
The hearts were perfused according to Langendorff's method with
an oxygenated (95% O2, 5%
CO2) noncirculating Krebs-Henseleit solution of
the following compositions (mmol/L): NaCl, 118; KCl, 4.7;
CaCl2, 2.5; MgSO4, 1.6;
NaHCO3, 24.9;
KH2PO4, 1.2; glucose, 5.5;
Na-pyruvate, 2.0. Perfusion pressure was 60 mm Hg. A catheter
placed into the pulmonary artery drained the coronary
effluent perfusate that was collected for determination of
coronary flow and venous PO2
measurements. The left atrium was cannulated by an incision of the left
auricle. After a 15-minute equilibration period, the heart was switched
into the working mode, with the use of a filling pressure (preload) of
15 mm Hg at an afterload pressure of 60 mm Hg. The
mechanical performance of the hearts was stable for the whole
experimental period of 90 minutes.
Flow and pressure signals for computation were obtained from the PLUGSYS measuring system (Hugo Sachs Elektronik). Computation of data was performed with a sampling rate of 500 Hz, averaged every 2 seconds, by use of the software ACQuire Plus V1.21f (PO-NE-MAH).
For further characterization of pathophysiological
reactions of the heart, the external heart power (EHP) was measured and
calculated using the formula, EHPLV [mJ ·
min-1 ·
g-1]=pressure-volume work + acceleration
work={[SV · (MAP - LAP)]+[1/2 · SV ·
d · (SV/
r2e)2]}
· HR gLVwwt –1. SV indicates
stroke volume; MAP, mean aortic pressure; LAP, mean left atrial
pressure; d, specific weight perfusate (1.004
g/cm3); r, inner radius of aortic cannula; e,
ejection time; HR, heart rate; LV, left ventricle; LVwwt, left
ventricular wet weight. The function of the left ventricle
was altered by changing the aortic pressure (afterload) at constant
left atrial filling pressure (preload). By adjusting the Starling
resistance, the aortic outflow could be switched during 1 minute from
the fixed baseline afterload to a preset higher afterload producing
step-wise rises in mean aortic pressure.
Thereafter, the hearts were gently blotted to dryness, and the weights of the total heart, the left ventricle, and the right ventricle were determined. The basis of the left ventricle was stored in liquid nitrogen for determination of eNOS expression.
Expression of eNOS in the Left Cardiac Ventricle
Tissues were ground at the temperature of liquid nitrogen using
a microdismembranator (Braun) and the powders extracted for 1 hour on
ice with 10 mmol/L Tris-HCl, pH 7.4, containing 1% SDS and
protease inhibitors (complete, Boehringer
Mannheim). Debris was removed by a 30-minute
centrifugation at 4°C (>100 000g). 100
µg total of the protein extracts were subjected to SDS-PAGE
electrophoresis and transferred to nitrocellulose membranes (Hybond,
Amersham). The eNOS protein was detected by use of a specific antibody
(monoclonal anti–NOS-III, Transduction Laboratories) and visualized by
enhanced chemifluorescence with a commercially available kit
(Amersham). As a secondary antibody, an anti-mouse IgG antibody coupled
to alkaline phosphatase was used (Jackson ImmunoResearch Laboratories).
Chemifluorescence was analyzed and quantified by
scanning with a Fluorimager 595-system (Molecular Dynamics).
Endothelium-Dependent Relaxation in Isolated Rings
of the Thoracic Aorta
The method used was the same as previously
described.5
Measurement of NO-Release
The porphyrinic microsensor (detection limit 10 nmol/L for in
vitro NO measurements) was prepared as described
previously.7 8 The amperometric signal at constant
potential of 0.67 V was measured with a voltametric analyzer
(PAR model 273, Princeton Applied Research) interfaced with an
IBM 80486 computer with data acquisition and control software. Linear
calibration curves were constructed for each sensor from 2 · 10
nmol/L to 2 · 10 µmol/L NO, before and after in vitro
measurements, with the use of aliquots of saturated NO prepared as
described.9
An opened thoracic aorta ring was immersed in physiological solution and positioned under a dissecting microscope. A porphyrinic sensor was lowered on the surface of the observed blood vessel with the help of a stereotactic micromanipulator. This was indicated by a small (10 pA) and short (ms) piezoelectric signal. Two auxiliary electrodes (platinum and silver/silver chloride) were positioned in a physiological solution near the opened aortic strip. The concentration of NO decreased exponentially with distance and was undetectable at distances >130±20 µm from the endothelium.
Measurement of Superoxide Production
The superoxide (O2-)
concentration in aortic tissue was determined by a chemiluminescence
method.10 Each (0.8 to 1.5 mg) tissue sample was placed in
2 mL of HBSS adjusted to pH 7.4, then adequate lucigenin was added to
establish a concentration of 2.5 · 100 µmol/L. The
generated O2- was measured
after a 2-minute incubation (basal value) by addition of 10 µL of
1.2 · 100 mol/L A23187. Photons were counted during the
first 20 seconds after the addition of A23187 and were calibrated as
O2- concentration by
constructing standard curves based on photons emitted by
O2- stoichiometrically
generated by reaction of xanthine and xanthine
oxidase.11
Statistical Analysis
The data, except survival, are given as mean±SE. ANOVA was
used. Tukey's test was used for post-ANOVA multiple pair comparisons.
Cumulative survival was analyzed for differences according to
the Kaplan-Meier method, after which, Cox-Mantel log-rank test was
used. Null hypotheses were rejected at P<0.05.
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Results |
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Measurements of Body Weight and Systolic BP
The body weights of the rats (370 to 410 g) did not differ over the course of the experiment. At the start of the study when the SHR were 15 months old, they had a systolic BP of 173±4 mm Hg that remained unaltered in the placebo and control group until the end of the study, at 21 months of age. ACE inhibition with ramipril over 6 months significantly decreased systolic BP in SHR to 121±3 mm Hg, which was similar (115±8 mm Hg) to the systolic BP of untreated normotensive WKY.6
Cumulative Survival
Placebo-treated SHR began to die from
cardiovascular complications at an age of 15 months
and had all died after 21 months. Ramipril treatment at a BP lowering
dose of 1 mg · kg-1 ·
d-1 (at the age of 15 months, when the first
deaths of placebo-treated SHR occurred) extended the maximal
life- span of these animals to 30 months (Figure 1). This life expectancy is almost
identical to the lifespan of untreated normotensive
WKY.5
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,
antihypertensive dose of ramipril (1 mg · kg-1
· d-1). Percentage survival in SHR was significantly
enhanced with ramipril treatment vs placebo (Kaplan-Meier
analysis followed by Cox-Mantel log-rank test, ramipril)
2=48.44, P<0.05.
Interim Analysis after 21 Months
Heart weights (mg/100 g body wt) of ramipril-treated SHR were
significantly less than (total, 463±12; left ventricle, 356±10; right
ventricle, 63±2) age-matched placebos (total, 711±21; left ventricle,
511±16; right ventricle, 112±11) and less than controls (total,
707±26; left ventricle, 509±18; right ventricle, 110±9).
Markers of the renin-angiotensin system such as plasma renin activity and plasma Ang I concentration were significantly greater in treated SHR, whereas plasma Ang II and serum aldosterone concentrations and ACE activities in the serum, thoracic aortas, and right cardiac ventricles were significantly lower versus age-matched placebos and controls (Table).
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Isolated Working Heart Preparation
External heart work was significantly higher in hearts from
ramipril-treated animals versus hearts from controls or placebo-treated
SHR (Figure 2).
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indicates 15-month-old SHR at the beginning of the study
(control);•, placebo;
Isolated Thoracic Aorta
Endothelium-dependent relaxation in response to
acetylcholine was strongly impaired in potassium chloride precontracted
aortic rings from control animals (15-months-old) as well as from
placebo-treated SHR (21-months-old). This impaired relaxation was
significantly reversed by ramipril treatment (Figure 3).
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Expression and Activity of eNOS
Densitometric analysis of Western blots showed a
significant increase (5-fold) of the expression of eNOS in the left
cardiac ventricles of ramipril-treated animals versus controls and
placebo-treated SHR (Figure 4). The
expression of eNOS in control animals was not significantly different
from placebo-treated SHR.
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Long-term ACE inhibition with ramipril treatment increased the release of NO from freshly excised thoracic aortic rings (Figure 5A). NO released from the aortas of controls and placebo-treated SHR, after stimulation with the receptor independent calcium ionophore A23187, was 335±18 nmol/L and 340±20 nmol/L, respectively. Calcium ionophore stimulated NO concentration increased by 47% (to 500±10 nmol/L) in aortas of ramipril treated SHR. Under the same conditions, age-matched untreated normotensive WKY showed an aortic NO release of 580±40 nmol/L. Both the basal and total O2- concentrations (observed before and after stimulation of NO release with calcium ionophore) decreased slightly, but nonsignificantly, after ramipril treatment versus controls and placebo-treated animals (Figure 5B).
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Discussion |
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The present study documents that late treatment with the ACE inhibitor ramipril in a BP lowering dose (1 mg · kg-1 · d-1) extended life expectancy of SHR by 43%, which corresponds to the lifespan of normotensive placebo-treated WKY.6 The prime effect that contributes to this lifespan extension is, presumably, the normalization of BP followed by restoration of the endothelial function. Ramipril treatment of old SHR restored NO formation by the endothelium to a level of 500±10 nmol/L, which is similar to the level observed for untreated normotensive WKY rats. The restoration of NO production by the endothelium preceded a BP reduction with regression of left ventricular hypertrophy and improved heart function. The capability of the endocardium and the cardiac endothelium to produce optimal concentration of NO through changes in mechanical forces during each systolic and diastolic period of cardiac contraction is crucial in maintaining proper heart function.12 In addition to NO restoration, many other regulators, such as sympathic activity,13 endothelin1, and thromboxane A2,14 could be positively affected by inhibition of the renin-angiotensin system.
Because an activated renin-angiotensin system is implicated in the development and maintenance of hypertension and cardiac hypertrophy,15 it is not surprising that late ramipril treatment resulted in a regression of established myocardial hypertrophy, which is also reflected in improved cardiac function. However, the possibility cannot be excluded that the heart weight differences were caused by different interstitial and/or intracellular fluid volumes in the myocytes that were positively influenced by ramipril treatment. In addition to the regression of left ventricular hypertrophy, improved function in the rat heart could also be mediated by endothelium-derived kinins.16 17
An increase in bioavailability of NO in ramipril-treated animals seems to be caused by the increase of eNOS expression and not by the decrease of O2- production. This is in contrast to our prevention study, in which, after early, lifelong ramipril treatment, we found reduced O2- production, in addition to the upregulation of eNOS, in aortas of old SHR.6 The concentration of NO is significantly higher in the cardiovascular system of untreated WKY than in untreated SHR. This difference is caused by a much lower production of O2- in WKY than in SHR. The porphyrinic sensor only detects the net NO concentration (NO that is not consumed in fast chemical reaction with O2- and can freely diffuse to a target cell). This net NO concentration depends both on the expression of eNOS and on the accumulation of O2-.18 Preventive long-term treatment of hypertensive rats with ramipril5 6 showed similar results to those of the present study. However, late treatment, in contrast with early treatment, with ramipril did not decrease generation of O2-.
Thus, it can be assumed that in SHR late ramipril treatment upregulated eNOS leading to a higher NO availability, which, in turn, reversed the impaired endothelium-dependent vasodilation. This contributed to the lifespan extension of old hypertensive rats. Similar data were obtained with only a 3-month treatment of old SHR with the Ang II subtype AT1 receptor blocker losartan.19
It is conceivable that the ramipril-induced inhibition of the endogenous breakdown of kinins mediated the increase in survival, because co-treatment with the bradykinin receptor antagonist icatibant suppressed the enhanced aortic cGMP content after high- and low-dose treatment with ramipril.20 Furthermore, an upregulated eNOS was found in cultured endothelial cells incubated for 48 hours with 8-bromo-cGMP.21 Another candidate that contributes to the upregulation of eNOS expression induced by endogenous kinins might be cAMP. Increased endothelial cAMP is induced by forskolin and amplified by activation of a cAMP-dependent protein kinase, the bradykinin-induced synthesis of cGMP.22 Recently, upregulation of eNOS by ACE inhibition was also described in the human atrial myocardium.23
Conclusion and Clinical Implications
Results of the present study show that different beneficial
effects of late antihypertensive ACE-inhibitor treatment on
major cardiovascular functions might contribute to the
life- span extension of rats with a genetic form of hypertension.
The pivotal beneficial effects of ACE inhibition are BP reduction and
restoration of endothelial function. This is manifested
by a significantly greater NO formation, which is also crucial for
normal BP, the regression of cardiac left ventricular
hypertrophy, and the improvement of cardiac function.
Various molecular/biochemical mechanisms can be attributed to these
effects. Suppression of tissue ACE expression and activity decreases
(1) local Ang II concentrations, which are mainly related to
antihypertensive and antihypertrophic actions24 ; and (2)
increased local concentrations of kinins which may preserve cardiac
functions.16 In addition, the upregulation of eNOS
associated with subsequently enhanced NO availability provides
functional restoration of the endothelium. It remains
to be confirmed by the outcome of long-term preventive
ACE-inhibitor treatment of high-risk patients with
myocardial infarction and coronary artery disease whether these
beneficial effects observed in SHR, in particular the extended life
expectancy, are also achievable in humans.25
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Acknowledgments |
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This work was supported in part by grants from Hoechst Marion Roussel, Inc, The Public Health Service (HL-55397), and the Research Excellence Fund, Center for Medical Research, Oakland University.
Received December 21, 1998; first decision February 5, 1999; accepted March 23, 1999.
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I. Kouchi, O. Zolk, F. Jockenhovel, G. Itter, W. Linz, B. Cremers, and M. Bohm Increase in Gi{alpha} Protein Accompanies Progression of Post-Infarction Remodeling in Hypertensive Cardiomyopathy Hypertension, July 1, 2000; 36(1): 42 - 47. [Abstract] [Full Text] [PDF]
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