Research Article
Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability

https://doi.org/10.1016/j.jash.2017.02.007Get rights and content

Highlights

  • Carvedilol or amlodipine similarly attenuates short-term blood pressure variability.

  • Carvedilol or amlodipine prevented target organ damage associated with hypertension.

  • Attenuation of blood pressure variability contributes in the prevention of organ damage.

Abstract

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor β, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor β, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats.

Introduction

β-blockers have been the cornerstone in the treatment of arterial hypertension due to their ability to reduce cardiovascular-related mortality in clinical trials.1 However, updated guidelines of the Eighth Joint National Committee do not further recommend β-blockers for the initial treatment of hypertension, considering the higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to the use of an angiotensin receptor blocker.2 In addition, the National Institute for Health and Clinical Excellence has recently downgraded the use of β-blockers from the first-line agents for hypertension to the fourth-line add-on therapy, based on the findings from meta-analyses that show a lack of benefit of β-blockers compared with placebo or other antihypertensive drugs.1

The lack of clinical benefits of β-blockers in uncomplicated hypertension has been attributed to their lower ability to reduce central blood pressure (BP) and blood pressure variability (BPV).3, 4 Findings from the Conduit Artery Function Evaluation study suggest that treatment with antihypertensive regimen containing atenolol is less effective than an amlodipine-based treatment on central aortic pressure reduction despite similar impact on brachial BP.3 In addition, central pulse pressure was significantly associated with the degree of total cardiovascular events and the development of renal impairment, suggesting that the reduced ability of atenolol to reduce central BP might partially explain the lower protection from cardiovascular events.3

Findings accumulated in the last decades have established that an increase in BPV contributes to the development of target organ damage (TOD) associated with hypertension.5 It has been suggested that large BPV induces the activation of local angiotensin II and mineralocorticoid receptor systems and chronic myocardial inflammation, resulting in cardiac hypertrophy and fibrosis.6 Prospective clinical trials have revealed that antihypertensive agents may differ in their ability to control excessive BPV, suggesting that calcium channel blockers are more effective than other BP-lowering drugs for the reduction of short-term, midterm, and long-term BPV.7 A post hoc analysis of the ASCOT-BPLA has demonstrated that amlodipine is significantly more effective than atenolol in the reduction of short-term and visit-to-visit BPV, and these effects explain the lower risk of stroke and coronary events in amlodipine-treated patients with respect to subjects assigned to atenolol.4, 8 A recent review summarizing the effect of antihypertensive therapy on various types of BPV in hypertensive patients has concluded that calcium channel blockers are more effective than other antihypertensive agents for the attenuation of short-term and long-term BPV and may be considered a preferable treatment in reducing BPV measures in high-risk patients.9

Although the lack of beneficial effects of β-blockers on central BP and BPV explains their lower ability to protect the hypertensive patient from cardiovascular events, it is important to point out that almost all the negative findings were obtained in clinical trials using atenolol, a second generation β-blocker with adverse effects on metabolic parameters and lack of effect on central BP.10 Considering that β-blockers greatly differ in their pharmacokinetic and pharmacodynamic properties, the extrapolation of these results to third generation β-blockers, such as carvedilol and nebivolol, seems to be inappropriate. Recently, we have shown that acute administration of carvedilol or nebivolol induces a greater attenuation of short-term BPV than atenolol in sinoaortic-denervated rats.11

Taking into account these previous findings, the aim of the present study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on BP control, BPV, and TOD in a N-nitro-l-arginine methyl ester (L-NAME) rat model of secondary hypertension.

Section snippets

Preparation of Carvedilol and Amlodipine Formulation

Liquid formulations were prepared for oral administration of carvedilol and amlodipine. The formula of the carvedilol solution consisted of 0.5% (wt/vol) carvedilol (Droguerías Saporiti, Buenos Aires, Argentina), 10% (wt/vol) D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and 40% (vol/vol) propylene glycol. Amlodipine solution consisted of 0.5% (wt/vol) amlodipine (Droguerías Saporiti, Buenos Aires, Argentina) and 5% (wt/vol) TPGS. Vehicle solution was composed by 10% (wt/vol) TPGS

Effects of the Treatment on Indirect and Direct BP

Table 1 shows the results of indirect and direct determination of BP in normotensive Wistar rats and L-NAME hypertensive rats chronically treated with carvedilol, amlodipine, or vehicle. The analysis of tail-cuff BP measurements showed that both treatments reduced SAP compared to vehicle administration. Evaluation of direct hemodynamics parameters revealed that hypertension induced by L-NAME significantly increased HR and the treatment with carvedilol, but not amlodipine or vehicle was able to

Discussion

Chronic intake of L-NAME has been established as an experimental model of hypertension characterized by an increase of both BP and BPV12, 21, 22, 23, 24 and associated with TOD. Previous studies have shown that chronic blockade of nitric oxide synthase by oral intake of L-NAME increases wall thickness of the thoracic aorta, proinflammatory cytokines levels, TGFβ expression in coronary arteries, and relative wall thickness of the left ventricle.21, 25, 26, 27, 28, 29 Chronic oral treatment with

Acknowledgments

Diego Chiappetta, Martín Donato, Gabriela Berg, Ricardo Gelpi, Germán González, and Andrea Carranza y Carlos A Taira, are Career Investigators from CONICET, Argentina.

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    This work was supported by grants from Secretaría de Ciencia y Técnica, Universidad de Buenos Aires.

    Conflict of interest: The authors declare no conflict of interest.

    1

    Julieta S. Del Mauro and Paula D. Prince contributed equally to this work.

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