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BACKGROUND AND PURPOSE: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. EXPERIMENTAL APPROACH: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility. KEY RESULTS: IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2-like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG-nitro-l-arginine and a D1-like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum. CONCLUSION AND IMPLICATIONS: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction.
Assuntos
Dopamina , Óxido Nítrico , Ereção Peniana , Ratos Sprague-Dawley , Masculino , Animais , Dopamina/metabolismo , Óxido Nítrico/metabolismo , Ereção Peniana/efeitos dos fármacos , Ratos , Camundongos , Humanos , Camundongos Endogâmicos C57BL , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Piperazinas/farmacologia , Pênis/efeitos dos fármacos , Pênis/metabolismo , Relação Dose-Resposta a DrogaRESUMO
INTRODUCTION: Hydrogen sulfide (H2S), known as a third gasotransmitter, is a signaling molecule that plays a regulatory role in physiological and pathophysiological processes. Decreased H2S levels were reported in inflammatory respiratory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. H2S donors or drugs that increase H2S have emerged as novel treatments for inflammatory respiratory diseases. We previously showed that resveratrol (RVT) causes vascular relaxation and antioxidant effects by inducing H2S production. In the current study, we synthesized a new molecule Cpd2, as an RVT analog. We examined the effect of Cpd2 and its precursor chalcone compound (Cpd1) on H2S formation under both healthy and oxidative stress conditions in the lung, as well as vascular relaxation in the aorta. METHODS: Cpd2 synthesized from Cpd1 with microwaved in basic conditions. H2S formation was measured by H2S biosensor in the mice lungs under both healthy and pyrogallol-induced oxidative stress conditions in the presence/absence of H2S synthesis inhibitor aminooxyacetic acid (AOAA). The effect of compounds on vascular tonus is investigated in mice aorta by DMT myograph. RESULTS: RVT and Cpd2 significantly increased
Assuntos
Sulfeto de Hidrogênio , Doenças Respiratórias , Camundongos , Animais , Pirogalol/farmacologia , Antioxidantes/farmacologia , Resveratrol , Pulmão , Aorta , Sulfeto de Hidrogênio/farmacologiaRESUMO
High-calorie diet, alcohol, and multiple drug use increase reactive oxygen species (ROS) and cause liver damage. ROS are crucial in the initiation/progression of liver diseases. Antioxidants have beneficial effects but produce clinically complex results. The hydrogen sulfide (H2S) pathway is considered a promising therapeutic target since it plays role in the pathogenesis/treatment of liver diseases. Sildenafil exerts antioxidant and hepatoprotective effects by increasing specific antioxidants such as superoxide dismutase, glutathione peroxidase, and regulating the Keap1/Nrf2 pathway which are common mechanisms underlying the effects of H2S. We aimed to determine if H2S has a role in the hepatoprotective and antioxidant effects of sildenafil. The effect of sildenafil on endogenous H2S production was elucidated with an H2S microsensor in the presence/absence of pyrogallol-induced oxidative stress and H2S synthesis inhibitor aminoxyacetic acid (AOAA) in the liver. The relation between the antioxidant effect of sildenafil and H2S was determined by luminol and lucigenin chemiluminescence. Sildenafil increased L-cysteine-induced H2S synthesis in the healthy liver and prevented the pyrogallol-induced reduction in H2S production. Sildenafil decreased the ROS production induced by pyrogallol and its protective effect was inhibited by AOAA. These results reveal that H2S is a new pharmacological mechanism of action of sildenafil on the liver. Therefore, sildenafil can be a potential therapeutic agent in treating many liver diseases in which H2S bioavailability is impaired. Additionally, the hepatoprotective effect of sildenafil by increasing endogenous H2S synthesis advances our knowledge in terms of developing H2S-targeting molecules.