Key result
Cilostazol significantly attenuated the increase in mean pulmonary artery pressure (25.1 vs 35.1 mmHg) and right ventricular hypertrophy in the monocrotaline-induced pulmonary hypertension rat model, but not in the chronic hypoxia model.
Why the study?
Preventing pulmonary vascular remodeling is key in pulmonary hypertension, but whether cilostazol prevents monocrotaline- and chronic hypoxia-induced pulmonary hypertension was unknown.
Does cilostazol prevent the development of pulmonary hypertension in monocrotaline- and chronic hypoxia-induced rat models?
Does cilostazol prevent the development of pulmonary hypertension in monocrotaline- and chronic hypoxia-induced rat models?
Absolute Event Rate: 25.1% vs 35.1%
p-value: p=<0.05
Cilostazol prevents the development of pulmonary hypertension in an inflammatory (monocrotaline) rat model but not in a hypoxia-induced vasoconstriction model, suggesting its efficacy may depend on the underlying etiology.
Hypothesis-generating for cilostazol in monocrotaline pulmonary hypertension; leaves open model-specific effects and clinical translation.
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 (60 mg/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. Mean PAP (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.Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB in lung tissue was measured by 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 [mPAP 25.1±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 high 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. Conclusion: We found model differences in the effect of CLZ on PH development. CLZ might have a preventable 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 be dependent on PH etiology.
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Ito et al. (2021) studied Experimental Pulmonary Hypertension (n=181). Cilostazol vs. Rat chow without cilostazol was evaluated on Mean pulmonary artery pressure (mPAP) in MCT-induced PH model (p=<0.05). Cilostazol significantly attenuated the increase in mean pulmonary artery pressure (25.1 vs 35.1 mmHg) and right ventricular hypertrophy in the monocrotaline-induced pulmonary hypertension rat model, but not in the chronic hypoxia model.
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