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Background: Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats.Methods: Fifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed.Results: mPAP [35.1±1.7 mmHg (MCT) (n=9) vs. 16.6±0.7(control) (n=9) (P < 0.05); 29.1± 1.5 mmHg(CH)(n=10)vs. 17.5±0.5(control)(n=10)(P<0.05)], RV/LV+S[0.40±0.01(MCT)(n=18) vs. 0.24±0.01(control)(n=10)(P<0.05); 0.41±0.03(CH)(n=13) vs. 0.27± 0.06 (control)(n=10)(p<0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP25.1±1.1 mmHg(n=11) (P<0.05), RV/LV+S 0.30±0.01(n=14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats.Conclusions: We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.
本文/Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, 2‑174 Edobashi, Tsu, Mie 514‑8507, Japan
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DOIinfo:doi/10.1186/s12890-021-01710-4
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2022-08-08T06:02:54+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション