Anat Cell Biol.  2016 Mar;49(1):7-14. 10.5115/acb.2016.49.1.7.

Reduced immunoreactivities of B-type natriuretic peptide in pulmonary arterial hypertension rats after ranolazine treatment

• Lee JC
• Kim KC
• Choe SY
• Hong YM

• KMID: 2308927
• DOI: http://doi.org/10.5115/acb.2016.49.1.7

Abstract

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by sustained increase in the pulmonary arterial pressure and excessive thickening and remodeling of the distal small pulmonary arteries. During disease progression, structural remodeling of the right ventricular (RV) impairs pump function, creates pro-arrhythmic substrates and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an anti-anginal, anti-ischemic drug that has cardioprotective effects of heart dysfunction. RAN also has anti-arrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. Therefore, we hypothesized that RAN could reduce the mal-adaptive structural remodeling of the RV, and prevent triggered ventricular arrhythmias in the monocrotaline-induced rat model of PAH. RAN reduced ventricular hypertrophy, reduced levels of B-type natriuretic peptide, and decreased the expression of fibrosis. In addition, RAN prevented cardiovascular death in rat model of PAH. These results support the notion that RAN can improve the functional properties of the RV, highlighting its potential benefits in the setting of heart impairment.

Keyword

B-type natriuretic peptide; Heart; Pulmonary artery hypertension; Ranolazine; Right ventricles

MeSH Terms

Animals
Arrhythmias, Cardiac
Arterial Pressure
Death
Disease Progression
Fibrosis
Heart
Heart Ventricles
Hypertension*
Hypertrophy
Models, Animal
Myocytes, Cardiac
Natriuretic Peptide, Brain*
Pulmonary Artery
Rats*
Sodium
Vascular Diseases
Ranolazine
Natriuretic Peptide, Brain
Sodium

Figure

• 

  Fig. 1 Pulmonary vascular remodeling. Examples of hematoxylin and eosin stained lung sections (A, C group; B, M group; C, RAN group) and statistics for small pulmonary artery wall thickness (SPAWT) measurements (D). C group, control group; M group, monocrotaline group; RAN group, ranolazine group. n=10 for each group. *P<0.05 vs. C group, #P<0.05 vs. M group. Scale bars=50 µm.

• 

  Fig. 2 Representative images of right ventricle (RV) stained with Masson's trichrome from control group (C group) (A), monocrotaline group (M group) (B), and ranolazine group (RAN group) (C) at 28 days following the injection of monocrotaline (MCT). (G) Collagen content was greatly increased in the M group in comparison with the C group at 28 days. The RAN group showed a significant decrease in collagen content at 28 days. Panels (D), (E), and (F) are highpower views of panels (A), (B), and (C); fibrosis is colored blue. *P<0.05 vs. C group, #P<0.05 vs. M group. n=10 for each group. Scale bars=150 µm (A–C), 70 µm (D–F).

• 

  Fig. 3 Expression of B-type natriuretic peptide (BNP) mRNA in the right ventricle. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) of BNP is expressed in the control group (C group), monocrotaline group (M group), and ranolazine group (RAN group). No amplification product was found without prior reverse transcription reaction or in water controls (data not shown). RAN group, BNP mRNA is decreased and the pattern of BNP mRNA expression is different. The sizes of RT-PCR products are indicated at left. Band densities were assessed and normalized after standardization of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) band densities to 1. Although samples were screened from five mice in each of the three groups, only a representative single band is shown. *P<0.05 vs. C group, #P<0.05 vs. M group.

• 

  Fig. 4 Western blot analysis of the levels of expression of B-type natriuretic peptide (BNP) and actin immunoreactivity in the right ventricle (RV). The semi-quantitative analysis confirms that ranolazine group (RAN group) exhibited increased levels of immunoreactivity of BNP in the RV (n=4–5 per group). C group, control group; RAN group, ranolazine group. *P<0.05 vs. C group, #P<0.05 vs. M group.

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