CELLULAR BASIS OF DYNAMIC, INFRAVESICAL OBSTRUCTION IN BPH - ROLE OF ADRENOCEPTOR BLOCKERS AND INTRACELLULAR 2ND MESSENGERS

The dynamic infravesical obstruction occurring in BPH is based on a al pha(1A)-adrenoceptor mediated stimulation of prostatic smooth muscle c ontractility. 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 nu cleotides by using the patch-clamp technique in enzymatically isolated human prostatic myocytes. Phenylephrine (PE) stimulated the transmemb ranous L-type Ca2+-current from 7.8 mu A/cm(2) up to 18.2 mu A/cm(2) s imultaneously increasing the free cytoplasmic Ca2+-concentration [Ca2](i) up to 1.9 mu M. Intracellular application of inositol 1,4,5-trisp hosphate (IP3) imitated while blockers of intracellular Ca2+-release s uppressed the PE mediated response. Therefore intracellular Ca2+-liber ation seems to be crucial for the dynamic obstruction in BPH. The alph a(1A)-induced stimulation of Ca2+-channel current was dose-dependently and reversibly suppressed by alfuzosin (IC50 0.39 +/- 0.11 nM) > tams ulosin (IC50 0.52 +/- 0.12 nM) > terazosin (IC50 1.85 +/- 0.32 nM) > d oxazosin (IC50 2.40 +/- 0.30 nM). In renal artery smooth muscle tissue the following ICS, were determined: terazosin (34.5 +/- 0.6 nM) > tam sulosin (46.7 +/- 3.5 nM) doxazosin (121.8 +/- 5.4 nM) > alfuzosin (21 2 +/- 7.2 nM) leading to selectivity-scores (renal artery-IC50/prostat e-IC50) of alfuzosin (543.59) tamsulosin (89.81) doxazosin (50.75) ter azosin (18.65). The cyclic nucleotides cAMP and cCMP inhibited the PE contraction up to 85%. The knowledge of cellular signal transduction e nables the development of innovative therapy strategies.