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Rapamycin Improves Vascular Remodelling in a Controlled Rat Model of Monocrotaline-induced Pulmonary Hypertension



Objective: Pulmonary arterial hypertension (PAH) is a serious disease characterized by progressive elevation of pulmonary arterial resistance, leading to right ventricular failure and death. We aimed to evaluate the effect of rapamycin (RAPA), a potent cell-cycle inhibitor, on exercise capacity, right ventricular hypertrophy, and pulmonary vascular remodeling.

Methods: Thirty-nine nine-week-old male Wistar rats (160–240 g) were divided into three groups: the control (n = 10), PAH control (n = 15), and PAH-RAPA (n = 14) groups. On the first day, 60 mg/kg monocrotaline was injected intraperitoneally to induce PAH in the PAH control and PAH-RAPA groups. On the 21st day, 3 mg/kg/day RAPA was started orally, and the animals were followed for 35 days. On the 35th day, the exercise capacity of the rats was analyzed through a modified forced swimming test. After measuring right ventricular systolic pressure using an open-chest method, the heart and lungs were excised and analyzed histopathologically for right ventricular hypertrophy and pulmonary vascular remodeling.

Results: RAPA treatment provided limited, but not significant, improvements in exercise capacity, right ventricular systolic pressure, and right ventricular hypertrophy. However, there was significant recovery in pulmonary artery muscular layer thickness with RAPA treatment (p = 0.049). On the 35th day, the mortality rate was 0% in the control group, 53.1% in the PAH control group, and 42.9% in the PAH-RAPA group. No statistically significant decrease was observed in mortality rates with RAPA treatment (p = 0.16); however, a significant recovery was noted in terms of median life span (p = 0.006).

Conclusions: PAH is a progressive disease that is not curable with current therapies. RAPA may have the potential reverse vascular remodeling and prolong life expectancy in cases of pulmonary hypertension.

18 May, 2015
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e-Published: 13 Aug, 2015


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