Poster Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

The role of drug efflux transporters on α1-adrenoceptor pharmacology of the mouse and rat prostate gland. (#350)

Carl W White 1 , Letitia M McGuiness 2 , Nicole T Eise 2 , Sab Ventura 2
  1. University of Western Australia, Perth, Western Australia, Australia
  2. Monash University, Melbourne, Victoria, Australia

Secretions of the prostatic gland make up approximately 20 - 30% of the ejaculate volume and play an important role in facilitating sperm transport, function and survival. Prostatic secretions are expelled into the ejaculate by contraction of the prostatic smooth muscle which is mediated by α­1L-adrenoceptors. The α1L-adrenoceptor functional phenotype, as seen in urinary tract tissues, is characterized by a low affinity for the α1-adrenoceptor antagonist prazosin. It is currently unknown as to why α­1-adrenoceptors in the prostatic smooth muscle display the α-1L phenotype instead of the normal α-1A phenotype. Prostatic smooth muscle cells have a significant population of α1A-adrenoceptors located intracellularly. In addition, prazosin is cell permeable and a known substrate for the efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP). We hypothesize that an intracellular population of α1A-adrenoceptors mediates contraction in prostate smooth muscle cells. Furthermore, these cells are able to actively efflux intracellular prazosin thus lowering the intracellular concentration of prazosin and decreasing the concentration available for binding to intracellular α1A-adrenoceptors. This may lead to the manifestation of the α1L-adrenoceptor functional phenotype. We tested this hypothesis using isolated preparations of mouse and rat prostate. Schild analysis of noradrenaline concentration-response curves in the absence and presence of prazosin (1–300nM) yielded affinity values of 8.80 in rats (n=6) and 8.68 in mice (n=3). Addition of the BCRP inhibitor, Ko-143 (1μM) increased the pA2 value in rat prostate to 9.83 (n=6) while genetic deletion of the BCRP transporter in mouse prostate increased the pKB for prazosin to 8.92 (n=5). These results confirm that mouse and rat prostate glands yield affinities to prazosin and tamsulosin which are consistent with the α1L-adrenoceptor functional phenotype. Moreover, blockade or deletion of the BCRP transporter, but not P-gp or extraneuronal uptake transporters, increases the affinity of prazosin towards that seen at α1A-adrenoceptors.