Background

Hypertension is associated with left ventricular hypertrophy (LVH) and diastolic dysfunction. The sympathetic nervous system (SNS) is strongly implicated in these alterations. The possible beneficial effect of a centrally mediated sympathetic inhibition on the diastolic function in severe hypertension has never been studied. We have evaluated the cardiac effects (remodeling, diastolic and systolic functions) of a long-term treatment with a centrally acting drug, rilmenidine, in a model of severe renovascular hypertension.

Methods

One-kidney, one-clip (1K,1C) Goldblatt hypertensive rabbits were randomized in two groups, one receiving rilmenidine (5 mg/kg/day) for 6 weeks and the other treated with vehicle only. Hemodynamic effects and left ventricular (LV) remodeling were evaluated by serial tail cuff pressure measurements, and echocardiography every 15 days. These measurements were followed up with invasive hemodynamic measurements and histological analysis.

Results

Rilmenidine induced a decrease of 8% in blood pressure, a significant bradycardia (19% at 6 weeks after treatment) and an 18% reduction in LV mass, without reduction of ejection fraction (EF). These effects were accompanied by an improvement of the diastolic function, as shown by isovolumic relaxation time and decrease in Tau index, an E/A ratio reversion, and an Ea velocity increase. Moreover, reduction in the atrial (A) and atrial reverse (Ar) velocities, without any effect on LV filling pressures, was observed.

Conclusions

In 1K,1C Goldblatt rabbits, which mimic most of the characteristics of human hypertensive cardiopathy, we have shown, for the first time, that a central inhibition of the SNS rapidly reverses cardiac hypertrophy and problems associated with primary LV relaxation, without negative inotropic action.

Methods

Experiments were performed in New Zealand white rabbits in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996).

Surgical procedure. Sixteen 4–6 week-old male rabbits (0.7–0.9 kg each in weight) were anesthetized with 2.5% isoflurane (AErrane, Baxter, Belgium) and xylazine (5 mg/kg, IP) (Rompun, Bayer, France). The right kidney was removed and the left renal artery isolated and stenosed (0.6 mm diameter ligation). Sham-operated animals (sham, n = 8) were submitted to the same procedure, except for the nephrectomy and renal artery stenosis.

Experimental protocol. Five weeks after surgery, cardiac anatomy and function were analyzed by echocardiography. Arterial blood pressure and HR were measured invasively (ear catheterization) and non-invasively (tail-cuff). Hypertensive 1K,1C rabbits (mean arterial pressure >105 mm Hg) were then separated into three groups for a 6-week-long infusion with subcutaneous osmotic minipumps (Alzet 2ML2; Charles Rivers, L'Arbresle France): (i) vehicle alone (n = 6), (ii) rilmenidine (5 mg/kg/day, n = 5) and (iii) metoprolol (30 mg/kg/day, n = 5) (Sigma-Aldrich, Isle, d'Abeau Chesnes, France). Echocardiography and non-invasive blood pressure measurements were performed every 2 weeks. At the end of the treatment, there was a follow-up with an invasive assessment of the arterial and ventricular pressures. All measurements were performed in conscious rabbits, except left ventricular pressure, which was measured in 2.5% isoflurane anesthetized animals. This last measurement was followed by cardiac morphometry and histology as previously described.⁶

Blood pressure measurements. For invasive measurements, a catheter was introduced in the central artery of the ear after local anesthesia (Emla 5%; AstraZeneca, Ruel Mulmaison, France) and connected to a transducer (Statham Db23; Gould Electronique, Courtaboeuf, France). The pressure signal was simultaneously recorded on a chart recorder (BS271; Gould Electronique, Courtaboeuf, France) and a data acquisition and storage system (Biocal, Bioseb, Chaville, France). HR, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) [MAP = DAP + 1/3 (SAP - DAP)] were continuously monitored. For non-invasive measurement, SAP and HR were recorded using a tail-cuff device (LE 5002; Bioseb, Chaville, France) after gentle shaving of the tail. The cardiac oxygen consumption was indirectly evaluated as the product of SAP and HR.

Echocardiography. Echocardiography was performed by applying standard practice guidelines, in rabbits placed in a seated position, using a Sonos 5500 (Philips, Andover, MA) equipped with a 12 MHz transducer and Doppler tissue imaging capability. The left ventricular (LV) mass was calculated using the following formula: LV mass = 0.61[(PW + S + EDD)³ - EDD³] + 2.⁷ The relative wall thickness (RWT) was calculated as RWT = 2 PW/EDD 100 and the cardiac output (CO) as CO = (D/2)² VTI HR (D = aortic diameter, VTI = time velocity integral). In the apical four-chamber view, transmitral and pulmonary venous flows were obtained in order to measure: Early (E) and Atrial (A) transmitral flow velocities, E-wave deceleration time, A-wave duration, isovolumetric relaxation time (IVRT), diastolic, systolic, and atrial reverse (Ar) peaks of the pulmonary venous flow velocities and Ar duration. In the same view, Doppler tissue imaging was applied in the pulsed Doppler mode to allow for a spectral display of Early (Ea), Atrial (Aa) and Systolic (Sa) mitral annulus velocities at its septal corner.

Left-ventricular catheterization. Under 2.5% isoflurane and local (lidocaïne) anesthesia, a fluid-filled catheter connected to a Statham Db23 transducer (which was in turn connected to a data acquisition and storage system) was introduced into the LV after direct cardiac puncture.

Data analysis. Baseline arterial pressure and HR of hypertensive and sham rabbits were compared using the unpaired Student's t- test. For continuous follow-up, the three groups (sham, vehicle, and rilmenidine) were compared using one-way analysis of variance followed by Bonferroni's test. Analysis of variance was applied to repeated measurements so as to to compare the evolution in each group. The metoprolol group was compared only against the rilmenidine group. Data are reported as mean values standard error of the mean (SEM). All calculations were performed using the GraphPad software, and P < 0.05 was considered significant.

Results

Baseline characteristics of 1K,1C rabbits 5 weeks after surgery

When compaed with sham-operated animals, the blood pressure and the HR of 1K,1C rabbits were significantly increased (Table 1). Left ventricular hypertension, characterized by an increase in LV mass/BW (P < 0.01), was observed. This LVH showed all the typical features of concentric LV hypertensive cardiopathy i.e., similar increases in the PW and SW thicknesses and lack of dilatation. The systolic function was preserved, as shown by the absence of any change in EF and CO (Table 1). In addition, we identified an abnormal left ventricular relaxation, characterized by a significant decrease in the E/A ratio (P < 0.05) and a significant reduction in the Ea/Aa ratio (P < 0.05), together with an augmentation of the IVRT (P < 0.01) (Table 1). No significant baseline differences were observed before drug administration between rabbits that were randomized in the three 1K,1C groups.

Table 1 - Characteristics of conscious sham-operated (n = 8) and 1K,1C rabbits (n = 16), 5 weeks after surgical procedure.

Full table

Cardiovascular hemodynamic effects of rilmenidine

Rilmenidine significantly reduced the HR, as was shown by comparison with the vehicle group (-14% after 2 weeks of treatment, P < 0.01) (Figure 1a). The bradycardia was maintained until the end of the treatment and confirmed by invasive measurement (P < 0.05). A progressive reduction in the SAP was observed, but this was not of statistical significance (-12% at the end of treatment, tail-cuff) (Figure 1b). Similarly, the invasive blood pressure measurement showed a tendency toward a reduction in SAP (P < 0.09) when compared with the measurement in the vehicle group (Table 2). The myocardial oxygen demand, as assessed by the rate pressure product, diminished significantly (24%) after 6 weeks of treatment, when compared with the vehicle-treated group (Figure 1c).

Figure 1.

Effects of a 6-week treatment with vehicle or rilmenidine or metoprolol on heart rate (a), systolic arterial pressure (b), and rate pressure product (c) in conscious 1K,1C Goldblatt rabbits. *P < 0.05 and **P < 0.01 vs. sham group at the same time point; ***P < 0.05 and ^†P < 0.01 vs. rilmenidine group at the same time point; ^‡P < 0.05 and ^§P < 0.01 vs. baseline value in the same group.

Full figure and legend (25K)

Table 2 - Invasive measurement of blood pressures and heart rate at the end of the study, in conscious 1K,1C and sham-operated rabbits.

Full table

Rilmenidine had no effect on cardiac systolic function, as shown by the stability of EF and fractional shortening (Figure 2, Table 3). Slight increases in fractional shortening and EF were observed in vehicle-treated 1K,1C rabbits, probably as a consequence of the sustained afterload augmentation. The absence of negative inotropic effect of rilmenidine was confirmed by LV catheterization, which showed that dP/dtmax was similar among the three groups (3379 460 mm Hg/s, 3539 629 mm Hg/s and 2975 629 mm Hg/s in the sham, vehicle, and rilmenidine groups, respectively).

Figure 2.

Lack of rilmenidine effects on cardiac contractility in 1K,1C Goldblatt rabbits. M-mode cardiac imaging of the left ventricle of sham-operated, vehicle-, and rilmenidine-infused 1K,1C Goldblatt rabbits in a conscious state (from top downward).

Full figure and legend (65K)

Table 3 - Time course of change in systolic and diastolic function parameters in conscious sham (n = 8), vehicle (n = 6), rilmenidine (n = 5), and metoprolol (n = 5) groups during treatment.

Full table

In contrast, rilmenidine markedly improved LV filling parameters. From 2 weeks onward until the end of our protocol, the drug normalized the E/A and Ea/Aa ratios (Figure 3a,b). At the last point of measurement, the increase in IVRT and Ar velocity was prevented by rilmenidine, as compared to the measurements in vehicle-infused animals. The diastolic improvement was confirmed by a significant reduction in Tau index (P < 0.05) when compared with the vehicle group (Figure 3c). The left ventricular end-diastolic pressure remained unaffected by treatment (10 2 mm Hg, 10 3 mm Hg and 5 2 mm Hg in sham, 1K,1C-vehicle and 1K,1C-rilmenidine respectively; ns), thereby confirming the lack of increase in filling pressure in the 1K,1C rabbits.

Figure 3.

Improvement in the left ventricular diastolic function by a 6-week treatment with rilmenidine. (a) Doppler mitral inflow patterns, at the end of the treatment, showing the decrease in the E/A ratio and the IVRT increase in a conscious 1K,1C rabbit infused with vehicle (middle panel), compared with the sham-operated animal (upper panel). This abnormal pattern turned normal in the 1K,1C-rilmenidine treated rabbit (lower panel). (b) Rapid normalization of the mitral inflow left-ventricular filling by rilmenidine. (c) Normalization of the Tau index in an anesthetized 1K,1C-rilmenidine-treated rabbit. S, sham-operated rabbits (n = 8); V, 1K,1C infused with vehicle (n = 6); R, 1K,1C treated with rilmenidine (n = 5); M, 1K,1C treated with metoprolol (n = 5). *P < 0.05 and **P < 0.01 vs. S; ***P < 0.05 and ^†P < 0.01 vs. R; ^‡P < 0.05 vs. baseline.

Full figure and legend (46K)

Effect of rilmenidine on cardiac hypertrophy

In rilmenidine-treated rabbits, echocardiography identified a reduction in LV mass when compared with vehicle-treated animals (Table 4). At the end of the treatment, the echographic LV mass was 12% lower in rilmenidine-treated rabbits than in the vehicle-infused animals. This reduction was related to a diminution of the septal and PW thicknesses, the EDD being similar in the two 1K,1C groups. The conclusion that can be drawn is that the RWT was significantly reduced by rilmenidine (Table 4). The echocardiographic results were confirmed by direct morphometric analysis, showing an 18% reduction in the LV weight (6.1 0.3 g vs. 7.4 0.5 g in 1K,1C-vehicle, P < 0.05) and a 16% decrease in the LV weight/body weight ratio (2.1 0.1 g/kg vs. 2.5 0.2 g/kg in 1K,1C-vehicle, P < 0.05). The only possible explanation for the reduction in LV mass in the rilmenidine group as compared to the vehicle group was that rilmenidine had produced a significant reduction in the cardiomyocytes size (-23%, P < 0.01) (Figure 4a,b). This follows from the finding that the collagen surface related to LV was not reduced by the rilmenidine treatment (2.8 0.3% vs. 2.7 0.3% in 1K,1C-vehicle and 1K,1C-rilmenidine groups respectively, ns).

Figure 4.

Reduction in left-ventricular remodeling by rilmenidine. (a) Reduction of the cardiomyocyte size at the end of the treatment. (b) Transverse section of the LV in sham-operated (n = 8), vehicle- (n = 6) and rilmenidine-infused (n = 5) 1K,1C Goldblatt rabbits (from left to right). *P < 0.05 **P < 0.01 vs. sham group; ***P < 0.01 vs. rilmenidine group.

Full figure and legend (52K)

Table 4 - Comparison of cardiac remodeling between conscious sham (n = 8), vehicle (n = 6), rilmenidine (n = 5), and metoprolol (n = 5) group.

Full table

Hemodynamic and cardiac effects of metoprolol. After 2 weeks of treatment, metoprolol induced a reduction in systolic blood pressure similar to that induced by rilmenidine. However, after 4 and 6 weeks, the SAP reverted to the baseline value (Figure 1b). At the end of the treatment, invasive measurements confirmed the lack of antihypertensive effect (Table 2). At the same time, the LV mass, as measured by echocardiography, was much more significant in the metoprolol group than in the rilmenidine one (P < 0.05) (Table 4). This result was confirmed by direct morphometric analysis: LV weight and LV weight/BW ratio were higher in the metoprolol group (6.1 0.3 g and 2.1 0.1 g/kg in the rilmenidine group and 7.4 0.5 g and 2.4 0.2 g/kg in the metoprolol group, P < 0.05). Bradycardia, similar to what was observed in rilmenidine-treated animals, was also observed after the 6-week treatment with metoprolol (Figure 1a and Table 2). It was associated with an increase of E/A ratio, similar to the one observed in the rilmenidine group (Figure 3b). However, the Ea/Aa ratio was unchanged. At the end of the treatment, Ea velocity and Ea/Aa ratio were not increased in the metoprolol group when compared with the rilmenidine group (P < 0.05) (Table 3). However, we observed a significant increase in the Tau index in the metoprolol group (Figure 3c).

Discussion

In this study, rilmenidine was selected for three main reasons: (i) it is a second-generation central antihypertensive agent, (ii) it is clinically well-tolerated as compared with first generation compounds because of its lower sedative effect,⁸ and (iii) it is associated with good renal tolerance as compared with clonidine, even after long-term treatment.⁹ This last point is important because the 1K,1C Goldbaltt model is well known to exhibit kidney dysfunction.¹⁰ Only sparse and partial data were available concerning the diastolic effects after long-term rilmenidine treatment in hypertension.^11,12,13 In a short-term study, Koldas et al. observed a reversion of the early-to-late speed of ventricular filling ratio.¹³ In a two-year-long open study, Farsang et al. observed no beneficial effect of this compound on LV filling in hypertensive patients. However, the statistical power of this study was not sufficient for analyzing the effect of rilmenidine on cardiac diastolic dysfunction.¹² The present study was designed because rilmenidine has been shown to be hypotensive in normotensive rabbits.¹⁴ In this species, the effects of rilmenidine are linked to central activity in the rostral part of the medulla oblongata.¹⁵ Nevertheless, the sympathetic nervous system (SNS) activity and blood pressure are low in this species. The renovascular 1K,1C Goldblatt model is a model of hypertensive cardiopathy in which an overactivity of the SNS plays a crucial role.¹⁶ In this work 1K,1C rabbits demonstrated hypertension in association with LVH. This hypertrophy exhibits typical features of hypertensive cardiopathy i.e., a concentric LVH with increased absolute and relative wall thicknesses. This hypertrophy is caused solely by an increase in the size of cardiomyocytes, given that collagen density was shown to be unaffected. Moreover, in all hypertensive animals we observed an abnormal relaxation quite similar to the one observed in human hypertensive cardiopathy.¹⁷ We observed an increase in the IVRT and decreases in the early-to-late speed of ventricular filling ratio (E/A) and the early-to-late speed of annular mitral movement ratio (Ea/Aa). We did not ever observe diastolic dysfunction without cardiac hypertrophy, probably because of the rapidly progressive increase in the blood pressure. The filling pressures were not increased, as was demonstrated by the normal values of end-diastolic pressure and Ar duration. This phenomenon could be explained by the lack of myocardial fibrosis, as shown by histological analysis (data not shown).

In hypertensive 1K,1C Goldblatt rabbits, the long-term 5 mg/kg/day rilmenidine treatment (dose in accordance with Parkin et al.¹⁴), induced significant bradycardia. This result is similar to previous clinical and pre-clinical data in essential hypertension.^12,18 A link between the extent of the bradycardia and cardiac hypertrophy has been suggested,¹² thereby indicating that rilmenidine could induce a greater reduction of the HR in rabbits that exhibit LVH. This result could explain why rilmenidine did not reduce the HR in normotensive rabbits.¹⁴

Starting from 2 weeks after commencement of the rilmenidine treatment, we observed a progressive decrease in wall thicknesses, and after 6 weeks the LV mass was significantly reduced. The LVH reduction could be explained by the slight reduction in afterload. However, after 2 weeks of treatment with metoprolol, although the hypotension was similar to what was observed in the rilmenidine group, the wall thicknesses were unchanged. Some studies have shown that there is a lack of correlation between hypotension and the reduction in LV mass. It is now obvious that the rapid development of cardiac hypertrophy in arterial hypertension is partly mediated by an equal stimulation of - and -adrenoceptors rather than by hemodynamic changes only.^2,19 Therefore the inhibition of the SNS overactivity by rilmenidine would permit a direct and rapid effect on cardiac tissue.

Rilmenidine induced a rapid improvement of the early diastolic filling. Indeed, we observed a significant reduction in IVRT and Tau index, and an increase in Ea peak velocity of the mitral annulus. Many factors could explain the diastolic effects of rilmenidine.

The first is the slight reduction in arterial pressure; indeed, some studies have shown that, in untreated early essential hypertension, abnormal LV filling was related to the level of the blood pressure.²⁰ However, Alli et al. showed that, in hypertensive patients, a reduction in arterial pressures with prazosin had no beneficial effect on diastolic function.²¹ In our study, the hypotensive effect would not be sufficient to modify LV filling. After 2 weeks, the hypotensive effect produced by metoprolol was not associated with an improvement in the LV filling; this is in contrast to the results obtained with rilmenidine.

The second factor is an improvement related to bradycardia. The HR reduction could contribute to a better diastolic filling. Schobel et al. showed that monotherapy with an - or a -blocker led to similar hypotensive and antihypertrophic effects. However, a significant improvement in LV filling was obtained only in patients treated with the -blocker, and a link with bradycardia was suggested.² However, bradycardia alone would not be sufficient to account for the improvement in the LV filling; in fact, after 6 weeks of metoprolol treatment, bradycardia was associated with a worsening of the diastolic function, as confirmed by an increase of the Tau index and a lack of reversion of the Ea/Aa ratio. Moreover, the single -adrenergic blocking by doxazocin in hypertensive subjects reduced cardiac hypertrophy and increased the ratio between early and atrial peak velocities of transmitral flow, without any reduction in HR.²²

The third factor implies a link between diastolic improvement and the antihypertrophic effect of rilmenidine, as suggested by experiences with other drugs.^3,23 Nevertheless, Matsui et al. showed that the antioxidant hydroxy-tempo improved diastolic parameters without reducing either cardiac hypertrophy or blood pressure.²⁴ Moreover, the acute single administration of clonidine in hypertensive patients improved diastole without, of course, reducing hypertrophy.²⁵ Nevertheless, data from our study suggest that the effects of rilmenidine on diastolic function could be due to the link between cardiac mass reduction and simultaneous withdrawal of the stimulation from - and -adrenergic receptors. This hypothesis is supported by the results obtained with metoprolol. In our model, a reduction in LVH seems necessary for improving diastolic function. This is evident from the finding that a 6-week metoprolol treatment, at a dose of 30 mg/kg/day, had no effect on LV mass, but there was an observable alteration in the LV relaxation. This absence of LVH reduction was not because of an insufficient dose; we employed here a higher dose than is usually used in rabbits.²⁶ Moreover, we observed the deleterious effect of the -blocker on the diastolic function. In fact, -adrenergic stimulation increases lusitropy by stimulating the phosphorylation of phospholamban and increasing Ca²⁺ uptake by SERCA.²⁷ An inhibition of this phosphorylation by metoprolol would induce an alteration of the LV relaxation, that is usually compensated by its antihypertrophic and hemodynamic effects. Similarly, an earlier study performed in 1K,1C rabbits has also identified the lack of antihypertrophic and hemodynamic effects of a curative treatment with the -blocker, pindolol.²⁸ In this model, the low efficiency of -blockers could be explained by the high SNS activity targeting -adrenergic receptors, in the vascular wall as well as in cardiac tissue. Similarly, a clinical study in hypertensive patients showed a greater improvement in the LV filling when combined - and -blocking was used rather than a -blocker alone.²⁹ Therefore, the myocardial -adrenergic stimulation would thwart the beneficial effects of the -adrenergic inhibition.

In summary, the present work is the first one showing that a long-term treatment with rilmenidine rapidly reverses cardiac hypertrophy and the impairment of LV relaxation in severe hypertension. These effects can be the result of hemodynamic activity as well as to a suppression of the catecholamine effects on all their targets in the myocardium. This work could open the way to long-term clinical trials with rilmenidine in hypertensive patients with diastolic dysfunction as a primary goal or objective.

DISCLOSURE

The authors declared no conflict of interest.

References

1. Aeschbacher BC, Hutter D, Fuhrer J, Weidmann P, Delacretaz E, Allemann Y. Diastolic dysfunction precedes myocardial hypertrophy in the development of hypertension. Am J Hypertens 2001; 14:106–113. | Article | PubMed | ISI | ChemPort |
2. Schobel HP, Langenfeld M, Gatzka C, Schmieder RE. Treatment and post-treatment effects of - versus -receptor blockers on left ventricular structure and function in essential hypertension. Am Heart J 1996; 132:1004–1009. | Article | PubMed | ChemPort |
3. Kobayashi M, Machida N, Mitsuishi M, Yamane Y. -blocker improves survival, left ventricular function, and myocardial remodeling in hypertensive rats with diastolic heart failure. Am J Hypertens 2004; 17:1112–1119. | Article | PubMed | ChemPort |
4. Nodari S, Metra M, Dei Cas L. -blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail 2003; 5:621–627. | Article | PubMed | ChemPort |
5. Gosse P, Roudaut R, Herrero G, Dallocchio M. -blockers vs. angiotensin-converting enzyme inhibitors in hypertension: effects on left ventricular hypertrophy. J Cardiovasc Pharmacol 1990; 16(Suppl 5):S145–S150.
6. Thomas L, Gasser B, Bousquet P, Monassier L. Hemodynamic and cardiac anti-hypertrophic actions of clonidine in Goldblatt one-kidney, one-clip rats. J Cardiovasc Pharmacol 2003; 41:203–209. | Article | PubMed | ISI | ChemPort |
7. Plehn JF, Foster E, Grice WN, Huntington-Coats M, Apstein CS. Echocardiographic assessment of LV mass in rabbits: models of pressure and volume overload hypertrophy. Am J Physiol 1993; 265:H2066–H2072. | PubMed | ChemPort |
8. Safar ME. Rilmenidine: a novel antihypertensive agent. Am J Med 1989; 87:24S–29S. | Article | PubMed | ChemPort |
9. Lins RL, Daelemans R, Dratwa M, Verbeelen D, Sennesael J, Brisgand B, Lameire N. Acceptability of rilmenidine and long-term surveillance of plasma concentrations in hypertensive patients with renal insufficiency. Am J Med 1989; 87:41S–45S. | Article | PubMed | ChemPort |
10. Akabane S, Natsume T, Matsushima Y, Deguchi F, Kuramochi M, Ito K. Alterations in renal Na+K+ATPase activity and [3H]ouabain binding in Goldblatt hypertensive rabbits. J Hypertens 1985; 3:469–474. | Article | PubMed | ChemPort |
11. Sadowski Z, Szwed H, Kuch-Wocial A, Kubasik A, Januszewicz W, Krupa-Wojciechowska B, Polak G, Stejfa M, Dvorak I, Balazovjech I, Dubai G, Simon K. Regression of left ventricular hypertrophy in hypertensive patients after 1 year of treatment with rilmenidine: a double-blind, randomized, controlled (versus nifedipine) study. J Hypertens Suppl 1998; 16:S55–S62. | Article | PubMed | ChemPort |
12. Farsang C, Lengyel M, Borbas S, Zorandi A, Dienes BS. Value of rilmenidine therapy and its combination with perindopril on blood pressure and left ventricular hypertrophy in patients with essential hypertension (VERITAS). Curr Med Res Opin 2003; 19:205–217. | Article | PubMed | ISI | ChemPort |
13. Koldas L, Ayan F, Ikitimur B. Short-term effects of rilmenidine on left ventricular hypertrophy and systolic and diastolic function in patients with essential hypertension: comparison with an angiotensin converting enzyme inhibitor and a calcium antagonist. Jpn Heart J 2003; 44:693–704. | Article | PubMed | ChemPort |
14. Parkin ML, Godwin SJ, Head GA. Importance of imidazoline-preferring receptors in the cardiovascular actions of chronically administered moxonidine, rilmenidine and clonidine in conscious rabbits. J Hypertens 2003; 21:167–178. | Article | PubMed | ChemPort |
15. Head GA, Burke SL, Chan CK. Site and receptors involved in the sympathoinhibitory actions of rilmenidine. J Hypertens Suppl 1998; 16:S7–S12. | Article | PubMed | ChemPort |
16. Rauch AL, Campbell WG Jr. Synthesis of catecholamines in the hypothalamus and brainstem in one-kidney, one clip and two-kidney, one clip hypertension in rabbits. J Hypertens 1988; 6:537–541. | Article | PubMed | ChemPort |
17. Slama M, Susic D, Varagic J, Frohlich ED. Diastolic dysfunction in hypertension. Curr Opin Cardiol 2002; 17:368–373. | Article | PubMed |
18. Callens-el Amrani F, Paolaggi F, Swynghedauw B. Remodelling of the heart in DOCA-salt hypertensive rats by propranolol and by an -2 agonist, rilmenidine. J Hypertens 1989; 7:947–954. | Article | PubMed | ChemPort |
19. Zierhut W, Zimmer HG. Significance of myocardial - and -adrenoceptors in catecholamine-induced cardiac hypertrophy. Circ Res 1989; 65:1417–1425. | PubMed | ChemPort |
20. Phillips RA, Goldman ME, Ardeljan M, Arora R, Eison HB, Yu BY, Krakoff LR. Determinants of abnormal left ventricular filling in early hypertension. J Am Coll Cardiol 1989; 14:979–985. | PubMed | ChemPort |
21. Alli C, Di Tullio M, Mariotti G, Taioli E, Belli C, Radice M. Effects of long-term treatment with prazosin on left ventricular diastolic function in mild to moderate hypertension. Chest 1992; 101:181–186. | Article | PubMed | ChemPort |
22. Agabiti-Rosei E, Muiesan ML, Rizzoni D, Zulli R, Calebich S, Beschi M, Castellano M, Muiesan G. Reduction of left ventricular hypertrophy after longterm antihypertensive treatment with doxazosin. J Hum Hypertens 1992; 6:9–15. | PubMed | ChemPort |
23. Hoffmann U, Globits S, Stefenelli T, Loewe C, Kostner K, Frank H. The effects of ACE inhibitor therapy on left ventricular myocardial mass and diastolic filling in previously untreated hypertensive patients: a cine MRI study. J Magn Reson Imaging 2001; 14:16–22. | Article | PubMed | ChemPort |
24. Matsui H, Shimosawa T, Uetake Y, Wang H, Ogura S, Kaneko T, Liu J, Ando K, Fujita T. Protective effect of potassium against the hypertensive cardiac dysfunction: association with reactive oxygen species reduction. Hypertension 2006; 48:225–231. | Article | PubMed | ChemPort |
25. Stefanadis C, Manolis A, Dernellis J, Tsioufis C, Tsiamis E, Gavras I, Gavras H, Toutouzas P. Acute effect of clonidine on left ventricular pressure-volume relation in hypertensive patients with diastolic heart dysfunction. J Hum Hypertens 2001; 15:635–642. | Article | PubMed | ChemPort |
26. Frolov VA, Drozdova GA, Mustyatsa VF, Rieger P, Antoni Z, Kuzovkin AE. Possible mechanism of regression of myocardial hypertrophy. Bull Exp Biol Med 2001; 132:644–646.. | Article | PubMed | ChemPort |
27. Villars PS, Hamlin SK, Shaw AD, Kanusky JT. Role of diastole in left ventricular function, I: Biochemical and biomechanical events. Am J Crit Care 2004; 13:394–403.; quiz404–405. | PubMed |
28. Cimini CM, Gonzalez MA, Weiss HR. Reduction of cardiac hypertrophy in renal hypertensive rabbits with pindolol. J Pharmacol Exp Ther 1991; 257:541–546. | PubMed | ChemPort |
29. Dianzumba SB, DiPette D, Joyner CR, Cornman C, Townsend R, Mauro K, Weber E, Theobald T. Left ventricular filling in hypertensive blacks and whites following adrenergic blockade. Am J Hypertens 1990; 3:48–51. | PubMed | ChemPort |