Armin Aryannejad1, Ali Gandominejad2, Mohammadreza Tabary1, Nafise Noroozi1, Ata Abbasi3, Farnaz Araghi4, Razieh Mohammad Jafari5, Ahmad Reza Dehpour6. 1. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2. Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran. 3. Department of Pathology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran. 4. Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. 6. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpour@yahoo.com.
Abstract
BACKGROUND: The brain-stimulating agent modafinil acts through nitric oxide (NO) and adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, involved in the skin flap survival (SFS). The main aim of this study was to investigate the efficacy of modafinil on SFS in rats through the involvement of NO pathway and KATP channels. METHODS: Using controlled experiment study design, we enrolled a sample of Wistar male rats. Different doses of modafinil (10, 25, 50, and 100 mg/kg) were injected intraperitoneally (i.p.) before the surgery. L-NAME (non-selective nitric oxide synthase [NOS] inhibitor), aminoguanidine (inducible NOS inhibitor), and 7-nitroindazole (neuronal NOS inhibitor) were administered prior to modafinil. The role of KATP channels was determined by coadministering glibenclamide (KATP channel blocker) or cromakalim (KATP channel opener) with modafinil. The predictor variables were administration of different doses of modafinil, and the coadministration of modafinil with L-NAME, aminoguanidine, 7-nitroindazole, glibenclamide, and cromakalim. The main outcome variables included the percentage of necrotic area (PNA) in flap tissues, histopathological results, vascular endothelial growth factor (VEGF) immunohistochemical (IHC) staining, and nitrite concentrations. Appropriate statistics were computed considering p-value ≤ 0.05 significant. RESULTS: Modafinil 25 mg/kg was the most effective dose (PNA: 26 [95% CI: 19-33]) vs. control (PNA: 81 [95% CI: 71-92]) (p< 0.001). All NOS inhibitors significantly reversed the protective effect of modafinil (p< 0.001). Non-effective dose of cromakalim had a synergistic effect with the sub-effective dose of modafinil (10 mg/kg), while glibenclamide reversed the effect of modafinil 25 mg/kg (p< 0.001). CONCLUSIONS: Modafinil increases SFS mediated by NO pathway and KATP channels, which could therefore be a target to improve SFS.
BACKGROUND: The brain-stimulating agent modafinil acts through nitric oxide (NO) and adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, involved in the skin flap survival (SFS). The main aim of this study was to investigate the efficacy of modafinil on SFS in rats through the involvement of NO pathway and KATP channels. METHODS: Using controlled experiment study design, we enrolled a sample of Wistar male rats. Different doses of modafinil (10, 25, 50, and 100 mg/kg) were injected intraperitoneally (i.p.) before the surgery. L-NAME (non-selective nitric oxide synthase [NOS] inhibitor), aminoguanidine (inducible NOS inhibitor), and 7-nitroindazole (neuronal NOS inhibitor) were administered prior to modafinil. The role of KATP channels was determined by coadministering glibenclamide (KATP channel blocker) or cromakalim (KATP channel opener) with modafinil. The predictor variables were administration of different doses of modafinil, and the coadministration of modafinil with L-NAME, aminoguanidine, 7-nitroindazole, glibenclamide, and cromakalim. The main outcome variables included the percentage of necrotic area (PNA) in flap tissues, histopathological results, vascular endothelial growth factor (VEGF) immunohistochemical (IHC) staining, and nitrite concentrations. Appropriate statistics were computed considering p-value ≤ 0.05 significant. RESULTS:Modafinil 25 mg/kg was the most effective dose (PNA: 26 [95% CI: 19-33]) vs. control (PNA: 81 [95% CI: 71-92]) (p< 0.001). All NOS inhibitors significantly reversed the protective effect of modafinil (p< 0.001). Non-effective dose of cromakalim had a synergistic effect with the sub-effective dose of modafinil (10 mg/kg), while glibenclamide reversed the effect of modafinil 25 mg/kg (p< 0.001). CONCLUSIONS:Modafinil increases SFS mediated by NO pathway and KATP channels, which could therefore be a target to improve SFS.
Authors: Sung Huang Laurent Tsai; Ching-Wei Hu; Shih-Chieh Shao; Eric H Tischler; Olufunmilayo H Obisesan; Dominique Vervoort; Wei Cheng Chen; Jiun-Ruey Hu; Liang-Tseng Kuo Journal: Front Cardiovasc Med Date: 2022-05-23