Comparation of effects of cilomilast and tadalafil, phosphodiesterase inhibitors, on monocrotaline-induced pulmonary hypertension in rats

Aim: The pathogenesis of pulmonary arterial hypertension (PAH) is still not fully understood and the complex interaction between pulmonary endothelial dysfunction and inflammation is one of the main factors in the development of this disease. In this study, it was aimed to evaluate the effect of anti-inflammatory cilomilast (CIL) and vasodilator tadalafil (TAD) on PAH. Method: A total of 40 rats were divided into control, monocrotaline (MCT), MCT+CIL, MCT+TAD and MCT+CIL+TAD groups. Echocardiographic evaluation was performed to rats, right ventricular pressures were measured invasively and histopathological findings in the lung and heart were evaluated. Results: Tissue NO levels in MCT+CIL and MCT+TAD groups were similar to MCT group, 61.22 (35.66-116.08) and 59.28 (46.68-75.81) nmol/g versus 50.39 (34.54-69.42 nmol/g), p> 0.05], in the MCT+CIL+TAD group, it was found to be significantly higher 84.16 (51.39-93.53) nmol/g, p=0.01]. There was no difference between the groups in terms of left ventricle to right ventricle ratio (LV/RV) and pulmonary accleration time (PAT) (p=0.097 and p=0.074). RV pressures were significantly lower in the MCT+TAD and MCT+CIL+TAD groups compared to MCT group [31(25-36), 33(26-42) and 43(39-59) mmHg respectively, p<0.05]. RV pressures remained high in the MCT+CIL group [38(31-45) mmHg] just like MCT group (p>0.05). Histopathologically, infiltration in the MCT+CIL and MCT+TAD groups was similar to the MCT group; in the MCT+CIL+TAD group, it was found to be significantly decreased compared to the MCT group (p=0.022). The pulmonary artery wall thickness measured in the MCT +CIL group was similar to that in the MCT group, but significantly decreased in the MCT+TAD and MCT+CIL+TAD groups (p<0.001 and p=0.005). Conclusion: In PAH induced by MCT, no significant effect of CIL alone on right ventricular systolic pressure and distal pulmonary artery wall thickening was observed. However, its use in addition to TAD improves inflammation and tissue NO levels. Different doses of this agent or other PAH models may be the subject of research for future studies. Key words; Cilomilast, Pulmonary arterial hypertension, Tadalafil, Monocrotaline, Rat.