Prostate cancer is the second most common cause of death from cancer in U.S. men, and advanced, hormone-refractory disease is characterized by painful osteoblastic bone metastases. Endothelin-1, more commonly known as a potent vasoconstrictor, is a normal ejaculate protein that also stimulates osteoblasts. We show here that plasma immunoreactive endothelin concentrations are significantly elevated in men with metastatic prostate cancer and that every human prostate cancer cell line tested produces endothelin-1 messenger RNA and secretes immunoreactive endothelin. Exogenous endothelin-1 is a prostate cancer mitogen in vitro and increases alkaline phosphatase activity in new bone formation, indicating that ectopic endothelin-1 may be a mediator of the osteoblastic response of bone to metastatic prostate cancer.

Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate.

1 We have systematically reviewed the presence, functional responses and regulation of alpha(1)-, alpha(2)- and beta-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes 2 Alpha(1)-adrenoceptors are only poorly expressed and play a limited functional role in the detrusor Alpha(1)-adrenoceptors, particularly their alpha(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates Alpha(1)-adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate 3 Alpha(2)-adrenoceptors, mainly their alpha(2A)-subtype, are expressed in bladder, urethra and prostate They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans Their overall post-junctional function in the lower urinary tract remains largely unclear 4 Beta-adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the beta(3)- and beta(2)-subtypes are important in the human bladder and urethra, respectively Beta(3)-adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment

/pdf/a1-a2-and-b-adrenoceptors-in-the-urinary-bladder-urethra-and-141o0muabo.pdf

α1‐, α2‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

α1-Adrenergic receptor regulation: basic science and clinical implications

The evolution of alpha blocker therapy for benign prostatic hyperplasia (BPH) has focused on improving convenience and tolerability. Indications for treating BPH include reversing signs and symptoms or preventing progression of the disease. The indication that most commonly drives the need for intervention is relief of lower urinary tract symptoms (LUTS) with the intent of improving quality of life. Alpha blockers are the most effective, least costly, and best tolerated of the drugs for relieving LUTS. Four long-acting alpha 1 blockers are approved by the Food and Drug Administration for treatment of symptomatic LUTS/BPH: terazosin, doxazosin, tamsulosin, and alfuzosin. All are well tolerated and have comparable dose-dependent effectiveness. Tamsulosin and alfuzosin SR do not require dose titration. Alfuzosin, terazosin, and doxazosin have all been shown to be effective in relieving LUTS/BPH independent of prostate size.

Alpha Blockers for the Treatment of Benign Prostatic Hyperplasia

Effects of nitric oxide on human and canine prostates

The objective of the present study was to characterize the binding and functional properties of endothelin (ET) receptor subtypes in the human prostate Human prostatic tissue was obtained from male subjects undergoing radical prostatectomy for low-volume prostate cancer The optimal assay conditions for characterizing human prostatic ET-1 binding sites on slide-mounted tissue sections were defined Maximal specific 125I-ET-1 binding was achieved after a 10-min preincubation, a 120-min incubation, and a washing procedure that consisted of a brief rinse and a 1-min wash The mean equilibrium dissociation constant (Kd) and density (Bmax) of ET-1 binding sites determined from six saturation studies were 072 +/- 013 nM and 404 +/- 69 fmol/mg of wet weight, respectively The mean Hill coefficient was 099 +/- 001, indicating that 125I-ET-1 identifies a single population of binding sites The pharmacology of 125I-ET-1 binding sites was characterized using competitive binding experiments The competition plots for ET-1 were best fit by a one-binding site model, whereas the plots for sarafotoxin 6C (S6C) and BQ123 were consistently best fit by a two-site model The mean Ki value of ET-1 was 034 +/- 012 nM The mean Ki values for the high and low affinity S6C binding sites were 050 +/- 009 nM and 084 +/- 028 microM, respectively The mean Ki values for the high and low affinity BQ123 binding sites were 551 +/- 105 nM and 249 +/- 65 microM, respectively The ratio of ETA to ETB binding sites was approximately 2:1 The ET receptor subtype mediating prostatic smooth muscle tension was investigated using agonist-antagonist competition studies ET-1, a nonselective ET agonist, elicited a potent contraction of prostate smooth muscle The pA2 of BQ123 for inhibiting ET-1-mediated contraction was 684 S6C, a selective ETB agonist, also elicited a potent contraction of prostate smooth muscle BQ123 at concentractions between 01 and 10 microM did not shift the S6C dose-response curve These functional studies suggest that both ETA and ETB receptors mediate the tension of prostate smooth muscle Endogenous ETS may be involved in the pathophysiology of bladder outlet obstruction in men with benign prostatic hyperplasia If this is the case, then ET antagonists may represent effective treatment for benign prostatic hyperplasia

Binding and functional properties of endothelin receptor subtypes in the human prostate.

The present study was designed to compare the binding and functional properties of alpha-1 adrenoceptors and the area density of smooth muscle in the human, canine and rat prostates. Chloroethylclonidine (CEC)-sensitive and -insensitive alpha-1 adrenoceptors were characterized on slide-mounted prostatic tissue sections using the ligand [3H]prazosin. The mean equilibrium dissociation constants (Kd) for [3H]prazosin binding sites were not significantly different among the three different species. The densities (Bmax) of CEC insensitive [3H]prazosin binding sites in the human, canine and rat prostates were 1.71 +/- 0.32, 0.35 +/- 0.04 and 0.84 +/- 0.11 fmol/mg of wet weight, respectively. The Bmax of CEC-sensitive [3H]prazosin binding sites in the human, canine and rat prostates were 1.32 +/- 0.83, 0.44 +/- 0.11 and 0.25 +/- 0.10 fmol/mg of wet weight, respectively. The contractile response elicited by the rat prostate in the presence of phenylephrine was consistently negligible. The mean maximal force after phenylephrine challenge (phenylephrine Emax) in the human and canine prostates were 0.125 +/- 0.025 g of force/mm2 cross-sectional area and 0.096 +/- 0.014 g of force/mm2 cross-sectional area, respectively. CEC inactivated 80 and 53% of the phenylephrine contractile response in man and dog, respectively. The mean percentage of area densities of smooth muscle in the human, canine and rat prostates were 38.8, 12.9 and < 1%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the binding and functional properties of alpha-1 adrenoceptors and area density of smooth muscle in the human, canine and rat prostates.

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Binding and functional properties of endothelin receptor subtypes in the human prostate.

A comparison of the binding and functional properties of alpha-1 adrenoceptors and area density of smooth muscle in the human, canine and rat prostates.