Faculty Bibliography

OBJECTIVES. To characterize nitric oxide synthase (NOS), which catalyzes nitric oxide (NO) production, in the human prostate using biochemical and immunohistochemical techniques. METHODS. NOS catalytic assay and NOS immunohistochemistry were performed on histologically verified nonmalignant prostate tissue obtained from the peripheral and transition zones of seven radical prostatectomy specimens. RESULTS. Biochemical analysis revealed NOS activity in the human prostate, with a greater amount in the peripheral zone than in the transition zone (P < 0.01). In both prostate zones, NOS was immunohistochemically localized to nerve fibers and ganglia coursing throughout the smooth musculature of the stroma and to subepithelial nerve plexuses. NOS immunoreactivity was also localized to glandular epithelium. CONCLUSIONS. The presence, activity, and distribution of NOS were described in two regions of the human prostate. The present evidence implicates NO in the automatic innervation and physiology of the human prostate. It is proposed that NO may modulate smooth muscle tone and secretory functions in the human prostate, although functional studies are needed to support these hypotheses

Randomized double-blind placebo controlled studies have consistently demonstrated the safety and effectiveness of selective alpha 1 blockers for the treatment of clinical BPH. Selective alpha 1 blockers relieve the symptoms of prostatism and decrease bladder outlet obstruction. The advantages of this class of drugs for the medical treatment of BPH include the extremely rapid onset of action, statistically and clinically significant effects on relevant outcome measures, adverse experiences that are generally infrequent, mild, and reversible, serum PSA levels are not affected, and hypertension is also effectively treated. The long-term effectiveness of selective alpha 1 blockers has recently been reported. Prostate smooth muscle tension is mediated by the alpha 1a (previously defined as alpha 1c) AR. The pharmaceutical industry is aggressively pursuing development of alpha 1a 'prostate' selective AR antagonists

The treatment of BPH has changed dramatically over the last decade. Industry has recognized the potential market for BPH therapies. Urologists have accepted and embrace the development of alternative treatment strategies. The combined resources and talents of industry and academic urology will lead to exciting future advances in this field. The optimal treatment of BPH requires not only new technology but a better understanding of the pathophysiology and natural history of this disease. Urologists are presently engaged in studies to better define these fundamental aspects of the disease process. The end result of these investigative efforts will be to the advantage of patients afflicted with BPH

The pathophysiology of clinical BPH has been attributed to bladder outlet obstruction resulting from the enlarged prostate. A direct relationship does not exist between prostate size, symptom severity, or bladder outlet obstruction. The pathophysiology of prostatism is most likely multifactorial. Elucidating the factors contributing to symptoms will likely provide the foundation for the development of new pharmacological alternatives for the medical treatment of BPH

OBJECTIVES. To determine whether nitric oxide (NO) is a mediator of prostatic smooth muscle activity. METHODS. Pharmacologic experiments using electrical field stimulation (EFS) were performed on strips of human and canine prostate. RESULTS. EFS alone elicited frequency-dependent contractions in preparations of human and canine prostates. The greatest contractile activity was achieved at 30 Hz. In the presence of 10(-5) M guanethidine (GUA) and 2 x 10(-6) M atropine (ATR), EFS elicited relaxation of canine prostate strips relative to baseline tension. A weak biphasic response consisting of initial relaxation and subsequent contraction relative to baseline tension was observed in the human prostate strips exposed to similar conditions. The smooth muscle activity observed in the presence of GUA plus ATR was attributed to nonadrenergic, noncholinergic (NANC) nerve transmission. 10(-4) M L-NG-nitroarginine methylester (NAME) significantly increased EFS-elicited NANC smooth muscle activity both in human and canine prostates. L-arginine, 10(-2) M, reversed the effect of L-NAME in human and canine prostates. Sodium nitroprusside, 10(-4) M, a donor of NO, caused relaxation of both human and canine prostates. The mean magnitude of the relaxant response/cross-sectional area in human prostate (2.64 +/- 0.4 g/cm2) was significantly greater than in the canine prostate (1.09 +/- 0.17 g/cm2) (P < 0.005). CONCLUSIONS. These results provide compelling evidence that NO plays a role in mediating contractile function of human and canine prostates

PURPOSE: We determined the tissue localization of the alpha 1a-adrenoceptor in the human prostate. MATERIALS AND METHODS: Autoradiographic localization of the alpha 1a-adrenoceptor in the human prostate was determined by performing competitive displacement experiments on slide mounted tissue sections using the ligand 125iodine-2-(-[4-hydroxyphenyl]-ethyl-aminomethyl)tetralone (125I-Heat), and the alpha 1-antagonists WB-4101 (4 x 10(-8) M.) and 5-carboxamido-2,6-diethyl-1,4-dihydro-3-[N-(3-[4-hydroxy-4-phenylpipe ridin- yl]propyl)]carboxamido-4-(4-nitrophenyl) (SNAP 5272, 3 x 10(-7) M.). Under these experimental conditions, WB-4101 and SNAP 5272 are selective alpha 1a/alpha 1d-adrenoceptor and alpha 1a-adrenoceptor antagonists, respectively. The autoradiographs were quantitatively analyzed using a computer image analysis system. RESULTS: Specific 125I-Heat binding associated with the epithelium and stroma were independently analyzed. WB-4101 and SNAP 5272 inhibited 100% of the specific 125I-Heat binding in the stroma, suggesting that all of the stromal alpha 1-adrenoceptors are of the alpha 1a subtype. WB-4101 inhibited none of the specific 125I-Heat binding in the epithelium, suggesting that the alpha 1-adrenoceptor in the epithelium is of the alpha 1b subtype. SNAP 5272 displaced only 25% of the specific 125I-Heat binding in the epithelium, suggesting that a relatively small percentage of the epithelial alpha 1-adrenoceptor is of the alpha 1a subtype. CONCLUSIONS: To our knowledge, our study represents the first cellular localization of the alpha 1-adrenoceptor subtypes in the human prostate using highly selective alpha 1-adrenoceptor antagonists and is consistent with the physiological observation that the activity of prostatic smooth muscle is mediated by the alpha 1a-adrenoceptor

PURPOSE: We attempt to determine whether terazosin is effective therapy for the treatment of prostatism-like symptoms in women. MATERIALS AND METHODS: A total of 29 women 47 to 79 years old with prostatism-like symptoms entered a randomized double-blind study comparing terazosin (14) versus placebo (15). The salient inclusion and exclusion criteria consisted of an American Urological Association (AUA) symptom score of 8 or more, post-void residual volume less than 300 ml. and absence of stress urinary incontinence. RESULTS: The baseline and final visit AUA symptom scores were 12.7 and 10.7 respectively, in the placebo group, and 16.4 and 13.6, respectively, in the terazosin group. The differences between the change in AUA symptom score in the placebo and terazosin groups were not clinically or statistically significant. CONCLUSIONS: Our study demonstrates that terazosin is not effective for the treatment of prostatism-like symptoms in aging women