Korean Circ J.  2010 Dec;40(12):659-664. 10.4070/kcj.2010.40.12.659.

Simvastatin, Sildenafil and Their Combination in Monocrotaline Induced Pulmonary Arterial Hypertension

• Lee DS
• Kim YK
• Jung YW

• KMID: 2225165
• DOI: http://doi.org/10.4070/kcj.2010.40.12.659

Abstract

BACKGROUND AND OBJECTIVES
Pulmonary arterial hypertension (PAH) is a life threatening disease characterized by progressive pulmonary arterial occlusion which may ultimately result in death. Currently, the available treatments are diverse, but no therapy alone can reverse the disease process although they may have some clinical benefits. This study was designed to investigate single and combination therapy of simvastatin and sildenafil, which have different mechanisms of action, in monocrotaline (MCT)-induced PAH. METERIALS AND METHODS: Rats were randomized to receive saline (control, n=8) or MCT treatment (n=32). MCT treated rats were randomized to vehicle, simvastatin (2 mg/kg/day), sildenafil (25 mg/kg/day) and a combination simvastatin and sildenafil (n=8, respectively). Three weeks later, hemodynamic study and histologic changes of pulmonary arterioles were measured. Proliferating cell nuclear antigen (PCNA) as well as Western blot for endothelial nitric oxide synthase (eNOS) were performed.
RESULTS
Systolic right ventricular pressure was significantly decreased in monotherapy groups (simvastatin and sildenafil) and the combination group compared to MCT group (p<0.05). Right ventricular hypertrophy and medial wall thickness of pulmonary arterioles were significantly attenuated with sole and combination therapy (p<0.05). However, combination therapy did not confer additive benefits over monotherapy. Altered PCNA or eNOS in lung tissue was normalized by either monotherapy or combination therapy.
CONCLUSION
The results suggest that either simvastatin or sildenafil has the therapeutic potential in MCT-induced PAH, although combination therapy of these two drugs has failed to show greater benefits in the study.

Keyword

Pulmonary circulation; Pulmonary hypertension; Simvastatin; Sildenafil

MeSH Terms

Animals
Arterioles
Blotting, Western
Hemodynamics
Hypertension
Hypertension, Pulmonary
Hypertrophy, Right Ventricular
Lung
Monocrotaline
Nitric Oxide Synthase Type III
Piperazines
Proliferating Cell Nuclear Antigen
Pulmonary Circulation
Purines
Rats
Simvastatin
Sulfones
Ventricular Pressure
Sildenafil Citrate
Hypertension, Pulmonary
Monocrotaline
Nitric Oxide Synthase Type III
Piperazines
Proliferating Cell Nuclear Antigen
Purines
Simvastatin
Sulfones

Figure

• 

  Fig. 1 Right systolic ventricle pressure. Simvastatin (SIM), sildenafil (SIL) and combination therapy (SIM+SIL) prevents the development of pulmonary arterial hypertension in monocrotaline (MCT) treated rats. However, combination therapy does not show additive effects over monotherapy. Values are expressed as mean±SD. *p<0.05 vs. control, †p<0.05 vs. MCT. RV: right ventricle.

• 

  Fig. 2 Ratio of the right ventricle (RV) to left ventricle (LV) plus septum weight. Monocrotaline (MCT)-induced RV hypertrophy was attenuated after simvastatin (SIM), sildenafil (SIL) and combination therapy (SIM+SIL). However, combination therapy did not show additional additive effects over monotherapy. Values are expressed as mean±SD. *p<0.05 vs. control, †p<0.05 vs. MCT.

• 

  Fig. 3 Medial wall thickness of pulmonary arterioles. Thickened medial wall in monocrotaline (MCT) treatment group was significantly reduced in simvastatin (SIM), sildenafil (SIL) and combination therapy (SIM+SIL). However, combination therapy did not show additional additive effects over monotherapy. Values are expressed as mean±SD. *p<0.05 vs. control, †p<0.05 vs. MCT.

• 

  Fig. 4 Immunohistochemical stains of proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Monocrotaline (MCT)-induced pulmonary hypertension showed prominent smooth muscle cell proliferation of the pulmonary artery. Simvastatin (SIM), sildenafil (SIL) and combination therapy (SIM+SIL) reduced cellular proliferation. TUNEL positive cells were not evident in all groups. Arrowheads, PCNA-positive cells.

• 

  Fig. 5 Western blots for eNOS in the lung. Expression of lung eNOS was significantly diminished in the monocrotaline (MCT)-induced pulmonary hypertension. However, eNOS expression was normalized to the control level by simvastatin (SIM) and sildenafil (SIL) treatment. However, combination therapy (SIM+SIL) did not show additional additive effects over monotherapy. Values are expressed as mean±SD. *p<0.05 vs. control, †p<0.05 vs. MCT, ‡p<0.05 vs. SIM and combination. eNOS: endothelial nitric oxide synthase.

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