REGULATION OF PROSTATIC SMOOTH-MUSCLE CONTRACTILITY BY INTRACELLULAR 2ND-MESSENGERS - IMPLICATIONS FOR THE CONSERVATIVE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA

The increased sympathetic neurotransmission in benign prostatic hyperplasia (BPH) results in a alpha(1C)-adrenoceptor-mediated increase in prostatic smooth muscle tone which seems to be responsible for the dynamic infravesical obstruction occurring in BPH. The prostatic smooth muscle contractions evoked by norepinephrine can be efficiently blocked by alpha(1)-adrenoceptor blockers. Moreover, an impressive number of clinical trials illustrated the beneficial results of alpha(1)-adrenoceptor blockers in the treatment of BPH. However, despite knowledge of al-adrenergic neurotransmission and the clinical application of its blockade by selective alpha(1)-adrenoceptor antagonists, very little is known about the intracellular pathways involved in the regulation of prostatic smooth muscle contractility. To study the intracellular mechanism of the alpha(1C)-adrenoceptor-induced prostatic smooth muscle contraction, the patch-clamp technique in the whole-cell configuration mode combined with the Fura-II fluorescence technique was used in human, enzymatically isolated smooth muscle cells obtained from patients undergoing transurethral resection of the prostate because of symptomatic BPH. Furthermore changes in prostatic smooth muscle contractility were registered in organ bath experiments. Application of the selective alpha(1)-adrenoceptor agonist phenylephrine (PE) increased the L-type Ca2+-channel current (I-Ca) dose dependently from 8 up to 18.5 mu A/cm(2), simultaneously elevating the free cytoplasmic Ca2+ concentration ([Ca2+](i)) up to 1.9 mu M. Pretreating the myocytes with pertussis toxin, an exotoxin of Bordetella pertussis which inactivates GTP-binding proteins (G proteins) of the G(i) and G(o) family by ADP ribosylation, reduced the PE-induced I-Ca stimulation by 71.5 +/- 5.6% (n = 21). Dialysis of the cytosol with the second messenger inositol-1,4, 5-trisphosphate (IP3), which releases Ca2+ from intracellular non-mitochondrial, IP3-sensitive Ca2+ pools, imitated the PE-evoked responses. Pretreating the myocytes with the Ca2+-release blockers ryanodine (10-100 mu M, n = 8), thapsigargin (0.1 mu M, n = 11) or low-molecular weight heparin (n = 14) largely attenuated the PE-evoked responses. The experimental results suggest a coupling of alpha(1)-adrenoceptors to phospholipase C-converting phosphoinositol-4,5-bisphosphate into diacylglycerol, an endogenous activator of the protein kinase C and IP3 which releases Ca2+ from intracellular stores stimulating I-Ca via Ca2+-calmodulin-dependent protein kinase induced phosphorylation of voltage-dependent Ca2+ channels. This knowledge could be of interest for conservative treatment in symptomatic BPH.