The increased sympathetic neurotransmission in benign prostatic hyperplasia (BPH) results in a α_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 α₁-adrenoceptor blockers. Moreover, an impressive number of clinical trials illustrated the beneficial results of α₁-adrenoceptor blockers in the treatment of BPH. However, despite knowledge of α₁-adrenergic neurotransmission and the clinical application of its blockade by selective α₁-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 α_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 α₁-adrenoceptor agonist phenylephrine (PE) increased the L-type Ca²⁺-channel current (I_Ca) dose dependently from 8 up to 18.5 µA/cm², simultaneously elevating the free cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) up to 1.9 µM. Pretreating the myocytes with pertussis toxin, an exotoxin of Bordetella pertussis which inactivates GTP-binding proteins (G proteins) of the G_i and Go family by ADP ribosylation, reduced the PE-induced lea 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 µM, n = 8), thapsigargin (0.1 µM, n = 11) or low-molecular weight heparin (n = 14) largely attenuated the PE-evoked responses. The experimental results suggest a coupling of α₁-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.

Since three-quarters of our patients were likely not to die of prostate cancer within the 10 years after surgery despite histological evidence of lymph node metastases, radical prostatectomy with or without hormonal therapy is a viable option for patients with local lymph node involvement, particularly in view of long-term survival.

We report a case of a 74-year-old patient who received 41 courses of maintenance therapy with gemcitabine over a length of 28 months for metastatic transitional cell carcinoma. One year earlier the patient had received three cycles of adjuvant cisplatin-based combination chemotherapy after nephro-ureterectomy for a locally advanced urothelial cancer of the right renal pelvis. This case demonstrates a paradigm shift in the palliative treatment of advanced urothelial cancer, with the implementation of more tolerable agents such as gemcitabine. Even elderly patients with impaired renal function may benefit in terms of tumor reduction and survival from systemic chemotherapy, which may be applied over a prolonged period of time.

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