In vitro blockade of α1-adrenergic receptors (α1-ADRs) affects testosterone production in Leydig cells of adult rats

Abstract

Testosterone, the main male reproductive hormone, is produced exclusively in testicular Leydig cells. Regulation of testosterone biosynthesis, i.e. testicular steroidogenesis, is a multi-compartmental process comprised of neuronal and complex endocrine, paracrine and autocrine signaling pathways, including adrenergic receptor signaling. It was shown recently that systemic in vivo blockade of α1-adrenergic receptors (α1-ADRs) disturbed testicular steroidogenesis. However, it is not clear whether the effects on Leydig cells are direct or caused by other organs/structures in vivo, and that Leydig cells are only indirectly affected by other mediators. The present study was designed to evaluate the relationship between α1-ADRs and testosterone synthesis in primary cultures of Leydig cells. To do this, prazosin, a potent and widely used antagonist of α1-ADRs was applied in vitro to treat primary cultures of Leydig cells freshly isolated from adult rat testes. The relationships between blockade of α1-ADRs receptors and cAMP and testosterone production by Leydig cells were analyzed. Results show that blockade of α1-ADRs in Leydig cells increases cAMP levels, but reduces the steroidogenic capacity of Leydig cells to produce testosterone. In the same cells, testosterone production was affected only at the highest concentration of prazosin. Application of adrenaline (a natural and potent agonist of all α/β-ADRs) during blockade overcame this reduction of testosterone production, but was not able to abolish the inhibitory effects of α1-ADRs blockade on the steroidogenic capacity of Leydig cells, suggesting that this effect is caused through α1-ADRs. The present data provide a new role for α1-ADRs in the regulation of testosterone biosynthesis in Leydig cells and new molecular insight into the relationship between α1-blockers and mammalian reproduction. The results are important in terms of human reproductive health and the widespread pharmacological application of prazosin, an important drug that has been used clinically for decades to treat hypertension, prostate hyperplasia, posttraumatic stress disorder, and scorpion stings, and holds promise as a pharmacologic treatment for alcohol dependence.