Priapism and voiding dysfunction in Sickle Cell Disease: pathophysiology and new drug candidates

Abstract

Priapism is an important clinical problem for patients with Sickle Cell Disease. Despite advances in understanding the pathophysiology of this condition, few studies have aimed at understanding the physiopathological mechanisms involved. To date, there is no satisfactory pharmacological therapy to prevent Priapism. Ideally, new prevention strategies should act on the pathophysiological basis of the disorder. In Sickle Cell Disease, experimental evidences show that reducing the bioavailability of Nitric Oxide (NO) in the penis is one of the main causes that contributes to Priapism. Recently, we have shown that a new NO donor compound, hybrid derived from thalidomide and hydroxyurea, prevents Priapism in transgenic sickle cell mice. In a continuing effort to identify new drug candidates for the treatment of Priapism, this project proposes to evaluate the pharmacological effect of new and promising NO donor compounds in transgenic sickle cell mice. These compounds are hybrids derived from thalidomide, resveratrol and furoxanic nucleus. As research advances in the understanding of Sickle Cell Disease, recent clinical researches have shown that patients with Sickle Cell Disease display Lower Urinary Tract Symptoms (LUTS). About 38% of patients exhibit overactive bladder. However, the pathophysiological mechanisms involved in voiding dysfunction in Sickle Cell Disease are scarce. In general, an important alteration that occurs in Sickle Cell Disease is increased oxidative stress and reduced NO bioavailability. In this context, the present project also proposes to study the alterations of the NO-cGMP signaling pathway and the role of oxidative stress in voiding dysfunction in transgenic sickle cell mice. In Sickle Cell Disease, the reduction of NO bioavailability by hemoglobin is a serious consequence of intravascular hemolysis. Clinical studies show a strong positive correlation between Priapism and increased levels of intravascular hemolysis in men with sickle cell anemia. However, to date, there are no experimental studies corroborating the clinical evidence. In the present project, we hypothesized that reducing the bioavailability of NO by free hemoglobin contributes to Priapism and to voiding dysfunction in Sickle Cell Disease. Therefore, the present project also proposes to study the role of intravascular hemolysis on lower genitourinary tract functions (penis, bladder and urethra) in transgenic sickle cell mice and model of intravascular hemolysis induced by phenylhydrazine in mice. (AU)