Published online before print March 9, 2009, doi: 10.1161/HYPERTENSIONAHA.108.126524
(Hypertension. 2009;53:775.)
© 2009 American Heart Association, Inc.
Original Articles |
Hemodynamic and Cardiac Effects of Chronic Eprosartan and Moxonidine Therapy in Stroke-Prone Spontaneously Hypertensive Rats
From the University of Montreal Hospital Research Center (CRCHUM) (S.M-D., A.M., P-A.P., M.J., J.G.); and Montreal Heart Institute (M-A.G., Y-F.S., A.C., J-C.T.), Departments of Medicine and Pharmacology, University of Montreal, Montreal, Quebec, Canada.
Correspondence to Suhayla Mukaddam-Daher, CRCHUM - St Luc (A-301), 264 Rene Levesque East, Montreal, Quebec, Canada, H2X 1P1. E-mail suhayla.mukaddam-daher{at}umontreal.ca
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Abstract |
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The renin-angiotensin and sympathetic nervous systems play critical interlinked roles in the development of left ventricular hypertrophy, fibrosis, and dysfunction. These studies investigated the hemodynamic and cardiac effects of monoblockade and coblockade of renin-angiotensin and sympathetic nervous systems. Stroke-prone spontaneously hypertensive rats (16 weeks old; male; n=12 per group) received the sympatholytic imidazoline compound, moxonidine (2.4 mg/kg per day); the angiotensin-receptor blocker eprosartan (30 mg/kg per day), separately or in combination; or saline vehicle for 8 weeks, SC, via osmotic minipumps. Blood pressure and heart rate were continuously measured by radiotelemetry. After 8 weeks, in vivo cardiac function and structure were measured by transthoracic echocardiography and a Millar conductance catheter, and the rats were then euthanized and blood and heart ventricles collected for various determinations. Compared with vehicle, the subhypotensive dose of moxonidine resulted in lower (P<0.01) heart rate, left ventricular hypertrophy, cardiomyocyte cross-sectional area, interleukin 1β, tumor necrosis factor-
, and mRNA for natriuretic peptides. Eprosartan reduced pressure (P<0.01), as well as extracellular signal–regulated kinase (ERK) 44 phosphorylation, Bax/Bcl-2, and collagen I/III, and improved left ventricular diastolic function (P<0.03). Combined treatment resulted in greater reductions in blood pressure, heart rate, left ventricular hypertrophy, collagen I/III, and inhibited inducible NO synthase and increased endothelial NO synthase phosphorylation, as well as reduced left ventricular anterior wall thickness, without altering the other parameters. Thus, in advanced hypertension complicated with cardiac fibrosis, sympathetic inhibition and angiotensin II blockade resulted in greater reduction in blood pressure and heart rate, inhibition of inflammation, and improved left ventricular pathology but did not add to the benefits of angiotensin II blockade on cardiac function.
Key Words: hypertension • hypertrophy • hemodynamics • natriuretic peptides • moxonidine • eprosartan
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Introduction |
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Increased activities of the renin-angiotensin-aldosterone system and the sympathetic nervous system have been considered as important contributors to the pathogenesis of hypertension, as well as to the development of left ventricular hypertrophy (LVH).1,2 Both angiotensin II, the primary effector molecule of the renin-angiotensin system, and the neurotransmitter norepinephrine exert hemodynamic effects by actions on several organs implicated in pressure and volume regulation, causing vasoconstriction and sodium retention. In addition, neurohormonal activation of cardiac adrenergic receptors and angiotensin type 1 (AT-1) receptors promotes growth of the cardiac muscle by direct hypertrophic and proliferative action on cardiomyocytes and fibroblasts and stimulation of biosynthesis of collagen and connective tissue and indirectly through inflammatory cell activation and stimulation of cytokine synthesis and release.3 During the early stages, LVH helps reduce wall stress, but sustained stimulation leads to progressive degenerative changes in hypertrophied cardiac myocytes and an abnormal accumulation of collagen deposition in the interstitial spaces, leading to ventricular stiffening. These changes give rise to ischemia, arrhythmia, left ventricular dysfunction, and, ultimately, heart failure.4
Randomized, controlled trials have convincingly shown that treatment of hypertension reduces cardiovascular risk, as well as mortality.5 Risk reduction is best obtained with treatments that provide effective lowering of elevated blood pressure and prevent hypertensive end-organ damage. Antihypertensive agents that inhibit the release or actions of norepinephrine, such as centrally acting sympatholytics and β-blockers, as well as those that interfere with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and AT-1 receptor blockers, are particularly effective in improving cardiovascular function and retarding/preventing LVH.6–10
The aims of the present study were to evaluate the additional benefits that concomitant AT-1 receptor blockade by eprosartan and imidazoline receptor agonism by moxonidine may confer on the heart function and structure and, more importantly, to explore the underlying signaling mechanisms involved in cardiac cell growth and death. Studies were performed on stroke-prone spontaneously hypertensive rats (SP-SHRs), a model of genetic hypertension largely used as an analog of the human severe hypertensive state with enhanced sympathetic nerve activity and LVH.11
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Methods |
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For details of the Methods section, please see the online data supplement, available at http://hyper.ahajournals.org.
Experimental Animals and Drug Treatment
The study was conducted in accordance with the Canadian Guidelines for the Care and Use of Laboratory Animals and was approved by the institutional animal protection committees at University of Montreal Hospital Research Center (CRCHUM) and Montreal Heart Institute. Male SP-SHRs (14 weeks old; 250 to 275 g; n=48) were housed at 22°C, maintained on a 12-hour light/12-hour dark cycle, and fed Purina Rat Chow (Ralston Purina) and tap water ad libitum. Animals were allowed 
1 week to adjust to the new environment. At 16 weeks of age, rats were randomly divided into 4 groups assigned to the following treatments: saline vehicle, moxonidine (2.4 mg/kg per hour), eprosartan (30.0 mg/kg per day), and eprosartan+moxonidine. The eprosartan dose was selected as the lowest dose that resulted in cardiac and renal protective effects in high-fat fed SP-SHRs.12 The dose of moxonidine was based on our previous studies as the lowest dose reversing LVH in spontaneously hypertensive rats.9 Moxonidine and eprosartan (Solvay Pharmaceuticals GmbH) were administered through osmotic minipumps (Alzet, Alzet Corp), as described previously.9,13
Water and food intake and urinary parameters were measured (metabolic cages) every 2 weeks and body weight every week. All of the rats were euthanized at 24 weeks of age. Blood was collected for the measurement of plasma atrial natriuretic peptide (ANP).14 The heart left ventricle (including septum) and right ventricle were weighed individually and snap frozen in liquid nitrogen.
Hemodynamic Measurements
Systolic, diastolic, and mean arterial pressures (MAPs) and heart rate were measured by radiotelemetry (Data Sciences International) in conscious rats (n=16) before and over a continuous period of 8 weeks, as described previously.13 At the end of the 8-week treatments, cardiac structure and function were analyzed by transthoracic echocardiography.15 On the following day, in vivo rat cardiac function was also assessed by a Millar Micro-Tip Catheter Transducer, as described previously.16
Histopathologic Measurements, Cardiac Proteins, and Gene Expression
Hearts were prepared for histological determinations, as described previously.9 Cytokines interleukin 1β (IL-1β) and tumor necrosis factor- (TNF-) were measured in left ventricles by quantitative sandwich ELISA (Biosource). Protein expression of total and phospho–extracellular signal–regulated kinase 42/44 (Cell Signaling) or total and phospho-Akt (phospho-Ser473), inducible NO synthase (iNOS), endothelial NO synthase (eNOS), phospho-eNOS (Ser1177), and collagen I and III (BD Transduction Laboratories) were measured by Western blotting. ANP and brain natriuretic peptide (BNP) gene expressions were measured by quantitative RT-PCR, as described previously.17
Statistical Analysis
All of the data obtained from treated rats were compared with corresponding age-matched, saline-treated controls. Statistical comparisons were performed by nonparametric 1-way ANOVA, followed by Dunnett’s multiple comparison test, using GraphPad Prism software 4.0. Statistical significance was determined at P<0.05. All of the data are reported as mean±SEM.
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Results |
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Physical and Hemodynamic Parameters
Basal parameters were not different among the groups. Water and food intake and urine volume, sodium, potassium, and creatinine excretion did not significantly differ among the groups (data not shown). Basal systolic, diastolic, and mean arterial pressures were 174±4, 127±5, and 151±5 mm Hg, respectively. Basal heart rate averaged 320±3 bpm. Figure 1 and Table 1 show blood pressure and heart rate changes in the 4 groups, presented as differences from corresponding baseline. Pressure was not altered by moxonidine, significantly reduced by eprosartan, and further reduced by combined treatment. Heart rate was reduced by moxonidine and combined treatment but not with eprosartan alone. Left ventricular mass normalized to tibia length (Table 1) and cardiomyocyte surface area (Figure 2) were significantly reduced by all of the treatments, the effects being more pronounced in the 2 eprosartan-receiving groups.
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Measurement of cardiac function by the Millar catheter revealed that right ventricular function was not affected by either treatment (data not shown). Left ventricular end-systolic pressure and the time constant of left ventricular isovolumic pressure decay, 
, were reduced (improved) by eprosartan, but not altered by moxonidine or combined therapy (Table 1). Echocardiographic parameters are summarized in Table 2. The thickness of the left ventricular anterior wall was significantly smaller in animals receiving the combination therapy. All of the treatments had no effects on left ventricular size and global systolic function, as assessed by left ventricular diameters, fractional shortening, volumes, and ejection fraction. On the other hand, transmitral E wave deceleration rate was only reduced by eprosartan, showing that eprosartan administered alone improved left ventricular compliance but not when combined with moxonidine. In addition, left ventricular isovolemic relaxation time and isovolemic relaxation time corrected for R-R interval were reduced in eprosartan-receiving groups, indicating that eprosartan alone or in combination with moxonidine improved left ventricular relaxation. Left ventricular myocardial performance index was significantly lower in animals treated with eprosartan alone, thus showing significantly improved left ventricular myocardial performance.
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Cardiac Proteins
Moxonidine, eprosartan, and eprosartan+moxonidine significantly reduced plasma ANP levels, as well as left ventricular ANP mRNA and BNP mRNA. The effects were more pronounced in the 2 eprosartan-receiving groups (Figure 3).
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The expression of cardiac proteins was evaluated by Western blot analysis. Densitometric measurements were reported as a percentage of the corresponding vehicle treatment (100%). Akt phosphorylation was not affected by either treatment, whereas extracellular signal–regulated kinase (ERK) 44 phosphorylation was mildly (88±3%), yet significantly (P<0.01), reduced by eprosartan alone. The apoptotic mitochondrial protein Bax was only reduced by eprosartan and eprosartan+moxonidine. Because Bcl-2 was not altered by treatments, Bax:Bcl-2 ratio, an index of apoptosis, was significantly (P<0.01) lower in the 2 eprosartan-receiving groups (Figure 4). The left ventricular phospho-eNOS:eNOS ratio, not significantly altered by moxonidine or eprosartan, was increased (P<0.04) by combined therapy. Also, only combined therapy reduced iNOS protein expression (Figure 5).
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Left ventricular IL-1β (110±10 pg/mg of protein) was significantly lower in moxonidine- and eprosartan-treated rats but not altered by combined therapy. On the other hand, TNF- (26±2 pg/mg of protein) was equally and significantly reduced by all of the treatments (Figure 6).
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Micrographs (Figure 7) show that collagen deposit was reduced by all of the treatments, the effect being more pronounced in the group receiving combined therapy. In addition, Western blotting revealed that collagen I was reduced by all of the treatments, whereas collagen III was significantly decreased by moxonidine, not altered by eprosartan, and significantly increased by combined therapy. These changes resulted in a significant reduction in the collagen I:III ratio in the eprosartan group (87±4%; P<0.01) and further reduction in the eprosartan+moxonidine group (73±6%; P<0.001; Figure 7).
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Discussion |
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This study assessed the effects of long-term treatment with 2 antihypertensive compounds, eprosartan and moxonidine, on cardiac structural abnormalities and cardiac function in SP-SHRs with severe hypertension and LVH. The administration of an antihypertensive dose of eprosartan regressed LVH and myocyte size; lowered plasma ANP and mRNA for ANP and BNP; decreased the mitochondrial Bax:Bcl-2 ratio; attenuated fibrosis and the level of inflammatory cytokines IL-1β and TNF-
; and improved cardiac dynamics, supporting that AT-1 receptor blockade is effective in severe hypertension. Moxonidine, at a subhypotensive dose, resulted in significant reductions of heart rate, LVH, cardiomyocyte size, and natriuretic peptide production and attenuated inflammatory IL-1β. Most important is that the addition of moxonidine to eprosartan resulted in greater lowering of blood pressure and heart rate and greater antihypertrophic and antifibrotic effects than eprosartan alone. These effects were associated with significantly elevated cardiac eNOS phosphorylation, reduced iNOS expression, and lower collagen deposit. Thus, in addition to greater blood pressure and heart rate reduction, combined treatment reduced inflammation and improved left ventricular pathology and most likely improved coronary circulation. Similar to human essential hypertension, the SP-SHR demonstrates a heredity predisposition to hypertension, enhanced sympathetic nerve activity, salt sensitivity, endothelial dysfunction, insulin resistance, dyslipidemia, and cardiac hypertrophy and fibrosis. Blood pressure is already elevated and LVH present by 12 weeks of age in SP-SHRs, and urinary norepinephrine excretion is higher than that of age-matched normotensive Wistar-Kyoto rats.18
SP-SHRs were used in the present study at 16 to 24 weeks of age, at the compensatory phase,11,19 when LVH can reduce wall stress and maintain cardiac function in the face of the hemodynamic overload. In agreement with previous reports, these rats had increased blood pressure and LVH.20 The present study also showed that SP-SHRs at this age have maintained cardiac function.
Treatment with eprosartan significantly lowered blood pressure and improved cardiac structure, attenuating LVH (indexed left ventricular mass and left ventricular anterior wall thickness). The reduction in wall thickness was associated with reduction in myocyte size and lower left ventricular natriuretic peptide expression, robust markers of cardiac hypertrophy.21 These effects were associated with improved left ventricular diastolic function, as evidenced by a reduced index, as well as improved left ventricular relaxation and compliance.
AT-1 receptor antagonists have also been shown to possess sympathoinhibitory properties. Among them, eprosartan has a higher affinity to presynaptic angiotensin receptors than other antagonists, thereby more effectively reducing sympathetic activity.22 The effects of eprosartan on the heart may also involve direct effects on the local renin-angiotensin-aldosterone system. During AT-1 receptor blockade, angiotensin II levels increase,23 whereas AT-2 receptors remain unblocked, allowing stimulation of the potentially beneficial effects mediated by AT-2 receptors, such as vasodilation, diuresis, and natriuresis, as well as growth-inhibitory, antihypertrophic, antifibrotic, and proapoptotic effects.24 The increased interaction of angiotensin II and AT-2 receptors has been postulated to contribute to the efficacy of angiotensin receptor blocker treatment.25
Neumann et al26 reported recently that blood pressure and sympathetic hyperactivity in patients with chronic renal failure were attenuated on treatment with eprosartan and further reduced and normalized by the addition of moxonidine. Moxonidine is a second-generation centrally acting sympatholytic imidazoline compound that reduces blood pressure by selective activation of I1 receptors in the rostral ventrolateral medulla and inhibition of sympathetic outflow to the periphery. In the present study, the pressure-independent effect of moxonidine was investigated using a subhypotensive dose. Indeed, this dose had no effect on blood pressure; nonetheless, it lowered heart rate. The effect occurred immediately after treatment initiation and was maintained throughout the study period. Heart rate has been shown to be associated with cardiovascular mortality in several epidemiological studies. Furthermore, the extent of heart rate reduction with β-blockade correlates with the magnitude of clinical benefits after myocardial infarction and in heart failure.27–29 Lower heart rate reduces myocardial oxygen demand and improves tissue perfusion through longer diastolic time. Lower heart rate may result from direct actions on the heart and reduction of sympathetic tone to the sinus node.30 Of note, the heart exhibits clusters of adrenergic cardiac cells devoid of the characteristic axonal elements of neurons. These cells can synthesize and release catecholamines in the absence of innervation and increase the rate of contraction of isolated myocytes in culture.31,32
The effects of moxonidine on the heart may also be mediated locally by cardiac I1 receptors.33 Cardiac imidazoline I1 receptors are functional, respond to in vivo pathophysiological and pharmacological stimuli,33,34 and can stimulate the release of ANP in vitro and in vivo.9,13,35 The direct implication of cardiac I1 receptors in these effects remains to be shown.
It is important to note that, compared with each drug alone, combined treatment resulted in greater reduction in LVH and collagen I:III ratio, as well as reduction in iNOS protein expression. Combined treatment also increased eNOS Ser1177 phosphorylation. eNOS is a calcium/calmodulin-dependent enzyme expressed and distributed in various cell types in the cardiovascular system. In the heart, eNOS is found in coronary and endocardial endothelial cells and cardiomyocytes. eNOS phosphorylation occurs in response to a variety of pathophysiological or pharmacological stimuli and is mediated by increases in intracellular calcium initiated by the activation of diverse G protein–coupled receptors. eNOS is phosphorylated by a number of kinases, including Akt/protein kinase B, adenosine monophosphate-activated-protein kinase (AMPK), protein kinase A, protein kinase C, protein kinase G, calcium/calmodulin-dependent protein kinase-2 (CaMK-2), and mitogen-activated protein kinases c-Jun-N-terminal kinase (JNK) and p38 but inhibited by ERK 42/44 mitogen-activated protein kinases.36 Whereas extracellular signal–regulated kinase and AKT appear not to be involved in eNOS phosphorylation in this study, further studies are required to identify other signaling pathways involved. However, regardless of the mechanism, increased eNOS Ser1177 phosphorylation can lead to increased NO bioavailability and vasodilation of the coronary microcirculation and prevent or delay vascular and cardiomyocyte damage.
Although combined treatment that resulted in greater reductions in blood pressure and heart rate inhibited iNOS and increased eNOS phosphorylation, as well as reduced left ventricular anterior wall thickness, only the degree of LVH regression and collagen deposit correlated with the degree of blood pressure change. These findings imply that the antifibrotic effect is pressure dependent. Several studies, however, have suggested direct cardioprotective effects of angiotensin receptor blockers, independent from their hemodynamic effect. Accordingly, it would be interesting to investigate the pressure-independent effects of eprosartan using a subhypotensive dose, alone and in combination with moxonidine.
Perspectives
These studies show that, in advanced hypertension complicated with cardiac hypertrophy and fibrosis, angiotensin II blockade improves cardiac structure and function. Combined angiotensin II blockade and imidazoline receptor agonism results in greater lowering of blood pressure and bradycardia, associated with antihypertrophic, antifibrotic, and antiinflammatory, as well as anti-ischemic, effects but does not add to the benefits of angiotensin II blockade on cardiac function. Thus, combined treatment can be beneficial in hypertrophic and ischemic hypertensive heart disease. On the other hand, combined treatment tended to offset some of the favorable modest effects of eprosartan on cardiac function and proteins, yet the changes remained within the normal range. The underlying mechanisms are currently under investigation in settings where cardiac function is already compromised.
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Acknowledgments |
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We acknowledge the assistance of the Cardiovascular Health Network of the Quebec Health Research Fund (FRSQ) for the measurements of blood pressure and cardiac function.
Sources of Funding
This work was supported by grants from Solvay Pharmaceuticals, GmbH (to S.M-D.), and the Canadian Institutes of Health Research and the Canadian Heart and Stroke Foundation (to S.M-D. and J.G.).
Disclosures
None.
Received November 19, 2008; first decision December 13, 2008; accepted February 10, 2009.
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