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Comparative Study
. 2025 Aug 9;25(1):591.
doi: 10.1186/s12872-025-05065-0.

Comparison of cilomilast, tadalafil, and both drug combinations in the treatment of monocrotaline-induced pulmonary arterial hypertension in rats

Necip Ermis  1 , Onural Ozhan  2 , Azibe Yıldız  3 , Zeynep Ulutas  1 , Hakan Parlakpinar  4 , Ahmet Ulu  5 , Burhan Ates  5 , Nigar Vardi  3 , Zeynep Kucukakcali  6 , Ahmet Acet  4
Affiliations
Comparative Study

Comparison of cilomilast, tadalafil, and both drug combinations in the treatment of monocrotaline-induced pulmonary arterial hypertension in rats

Necip Ermis et al. BMC Cardiovasc Disord. .

Abstract

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction and inflammation. This study aimed to evaluate the effects of cilomilast (CIL), a phosphodiesterase-4 inhibitor, and tadalafil (TAD), a phosphodiesterase-5 inhibitor, on PAH induced by monocrotaline (MCT) in rats.

Methods: Forty Wistar albino rats were divided into five groups: control, MCT, MCT + CIL, MCT + TAD, and MCT + CIL + TAD. PAH was induced via MCT, and treatments were administered orally from days 21 to 35. Hemodynamic parameters, right ventricular pressure (RVP), echocardiographic findings, and histopathological lung and heart tissue changes were assessed. Nitric oxide (NO) levels in lung tissue were also measured.

Results: Tissue NO levels were significantly greater in the MCT + CIL + TAD group than in the MCT group (p = 0.01). The RVP was lower in the MCT + TAD and MCT + CIL + TAD groups than in the MCT group (p < 0.05) but not in the MCT + CIL group. Histopathologically, lung perivascular infiltration and pulmonary artery wall thickness were significantly reduced in the MCT + CIL + TAD group, indicating an anti-inflammatory effect. However, CIL alone did not significantly impact pulmonary artery thickening or RVP.

Conclusion: CIL alone had no significant effect on PAH progression, but its combination with TAD improved inflammation scores and NO levels. These findings suggest that targeting inflammation alongside vasodilation may offer therapeutic benefits in PAH. Further studies with different doses and PAH models are recommended.

Keywords: Cilomilast; Monocrotaline; Pulmonary arterial hypertension; Rat; Tadalafil.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Ethical approval was obtained from the Experimental Animal Ethics Board at İnönü University (2016 A-114). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Parasternal long axis M Mode transechocardiographic view of the heart
Fig. 2
Fig. 2
Right ventricular pressure and ECG recording findings
Fig. 3
Fig. 3
Histological images of lung tissue from the control (A), MCT (B), MCT + CIL (C), MCT + TAD (D), and MCT + CIL + TAD (D) groups at 20X magnification. H&E-stained lung tissue sections of rats in each group (n = 8) were examined for mononuclear cell infiltration in 10 randomly selected areas. In the MCT group (B), perivascular infiltration (arrows) is noticeable. In MCT + CIL (C) and MCT + TAD groups (D), infiltration continues at a similar level to the MCT group. It is noteworthy that in the MCT + CIL + TAD group (E), infiltration decreased significantly
Fig. 4
Fig. 4
Histological images of lung tissue from the control (A), MCT (B), MCT + CIL (C), MCT + TAD (D), and MCT + CIL + TAD (D) groups at 40X magnification. In H&E-stained lung tissue sections of rats in each group (n = 8), the tunica intima-media thickness of at least 10 pulmonary arteries was measured from 6 different points. Arrows indicate the pulmonary arteriole
Fig. 5
Fig. 5
Histological images of cardiac tissue from the control (A), MCT (B and C), MCT + CIL (D), MCT + TAD (E), and MCT + CIL + TAD (F) groups at 20X magnification. H&E-stained cardiac tissue sections of rats in each group (n = 8) were examined for mononuclear cell infiltration in 10 randomly selected areas. It is noteworthy that in the MCT group, all groups had a similar histological appearance, except for mild infiltration (arrows)
Fig. 6
Fig. 6
Oxidative stress parameters of lung tissue: A Catalase, B Superoxide dismutase, C Total glutathione, and D Malondialdehyde. Data were expressed as mean ± standard deviation (n = 8) * Significant difference between all groups (p < 0.001), significant difference between MCT + CIL and MCT and MCT + TAD (p < 0.05). **Significant difference between all groups (p = 0.013), significant difference between MCT + CIL + TAD and all groups (p < 0.05). *** No difference between groups (p = 0.074). *****Significant difference between all groups (p < 0.001), significant difference between MCT + CIL + TAD and all groups (p < 0.05)
Fig. 7
Fig. 7
Nitric oxide levels from lung tissues. Data were presented as median (min-max) values (n = 8 rats per group)
See this image and copyright information in PMC

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