The effects of antifibrotic agent nintedanib on experimental priapism model in rats

Introduction: Priapism is an involuntary erection that exceeds more than 4 hours without sexual stimulation. Ischemic priapism which requires urological emergency intervention is characterized by low blood flow to the penis and is the most common type of priapism. In the event of ischemic priapism, tissue hypoxia and acidosis occur and progressively increase by the time. If immediate urological intervention is not performed, necrosis and fibrosis develops in the penile smooth muscles. After the fibrosis process, a decrease in erectile functions start to develop. Nintedanib, a low molecular weight triple tyrosine kinase inhibitor, inhibits the signaling of the Fibroblast Growth Factor (FGF), Platelet Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) receptors, which are effective in the development of idiopathic pulmonary fibrosis (IPF). It is used in the treatment of IPF due to these characteristics. Purpose: In our study, the rat model of priapism which progresses to penile smooth muscle necrosis and subsequent fibrosis was created and the effects of nintedanib which had effective results in the treatment of pulmonary fibrosis has been studied on the fibrosis process after priapism. Material and Method: The study was performed in Wistar albino type male rats. Experimental priapism model was created. The study consisted of five groups. Twelve rats were studied in each group. In each group, an erection model was created for 60 seconds with electrical stimulation (4 volts) and intracavernosal pressures were measured, while intra-carotid blood pressure monitoring was performed simultaneously. In the control group; only penectomy were performed, cavernosal tissue were examined histopathologically. In the pathology group; after 1 hour of ischemic priapism penectomy were performed and cavernosal tissue were examined. In the untreated pathology group, after 1 hour of ischemic priapism, rats were followed 6 weeks without treatment and were sacrificed. In the study group, after 1 hour of ischemic priapism, oral Nintedanib was given a dose of 60 mg/kg/day in the form of 2 doses per day and were sacrificed after 6 weeks. In the drug control group; oral Nintedanib were administered at a dose of 60 mg / kg / day in the form of 2 doses, without priapism, and were sacrificed after 6 weeks. Cavernosal tissues were evaluated by immunohistochemical and biochemical methods. Conclusion: When the results of pathological sections, electrophysiology, ELISA and Spectrophotometer were evaluated together, it was found that Nintedanib increased fibrosis after priapism and caused an erection defect. It is thought that this effect is especially due to the inhibition of VEGFR-2. Nintedanib, which is antifibrotic for the lung, was found to be profibrotic for penile tissues in the presence of a history of ischemia in cavernous tissues, and in normal conditions, it may decrease intracavernosal pressure and cause an erection defect. Key Words: Ischemic Priapism, Nintedanib, Penile Fibrosis, Priapism, Vascular Endothelial Growth Factor Receptor-2