Cellular basis of dynamic, infravesical obstruction in BPH: Role of adrenoceptor blockers and intracellular second messengers

The dynamic infravesical obstruction occurring in BPH is based on a alpha(1A)-adrenoceptor mediated stimulation of prostatic smooth muscle contractility. The present study yields the cellular mechanism of alpha(1A)-adrenoceptor induced prostatic smooth muscle contraction and the selectivity and potency of various adrenoceptor blockers and cyclic nucleotides by using the patch-clamp technique in enzymatically isolated human prostatic myocytes. Phenylephrine (PE) stimulated the transmembranous L-type Ca2+-current from 7.8 mu A/cm(2) up to 18.2 mu A/cm(2) simultaneously increasing the free cytoplasmic Ca2+-concentration [Ca2+](i) up to 1.9 mu M. Intracellular application of inositol 1,4,5-trisphosphate (IP3) imitated while blockers of intracellular Ca2+-release suppressed the PE mediated response. Therefore intracellular Ca2+-liberation seems to be crucial for the dynamic obstruction in BPH. The alpha(1A)-induced stimulation of Ca2+-channel current was dose-dependently and reversibly suppressed by alfuzosin (IC50 0.39 +/- 0.11 nM) > tamsulosin (IC50 0.52 +/- 0.12 nM) > terazosin (IC50 1.85 +/- 0.32 nM) > doxazosin (IC50 2.40 +/- 0.30 nM). In renal artery smooth muscle tissue the following ICS, were determined: terazosin (34.5 +/- 0.6 nM) > tamsulosin (46.7 +/- 3.5 nM) doxazosin (121.8 +/- 5.4 nM) > alfuzosin (212 +/- 7.2 nM) leading to selectivity-scores (renal artery-IC50/prostate-IC50) of alfuzosin (543.59) tamsulosin (89.81) doxazosin (50.75) terazosin (18.65). The cyclic nucleotides cAMP and cCMP inhibited the PE contraction up to 85%. The knowledge of cellular signal transduction enables the development of innovative therapy strategies.