Basu Chakrabarty

Tamsulosin modulates, but does not abolish the spontaneous activity in the guinea pig prostate gland

To examine the effects of the α1A‐adrenoceptor antagonist, tamsulosin, on spontaneous contractile and electrical activity in the guinea‐pig prostate gland.

Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate

Lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) are highly prevalent in older men, having a profound impact on patient quality of life. Current therapeutics for BPH/LUTS target neurogenic smooth muscle tone, but response is unpredictable and many patients fail to respond. Spontaneous myogenic tone is another component of smooth muscle contractility that is uncharacterized in human prostate. To better understand and improve the predictability of patient response, we defined myogenic contractility using human prostate specimens and examined the effect of existing therapeutics. We show that myogenic activity is present in the human prostate with the frequency of contractions in transition zone (TZ) specimens from BPH diagnosed patients approximately 160% greater than matched controls. α1-adrenoreceptor antagonists (Tamsulosin) and PDE5 inhibitors (Sildenafil) both significantly reduced myogenic contractile parameters, including frequency, with notable interpatient variability. Tamsulosin was more effective in older patients (R2 = 0.36, p < 0.01) and men with larger prostate volumes (R2 = 0.41, p < 0.05), while Sildenafil was more effective in younger men (R2 = 0.45, p < 0.05). As myogenic tone is significantly increased in BPH, therapeutics targeting this mechanism used with reference to patient characteristics could improve clinical outcomes and better predict patient response.

MP44-15 SPONTANEOUS MYOGENIC CONTRACTILITY IN THE HUMAN PROSTATE GLAND: IMPLICATIONS FOR THE TREATMENT OF LUTS ASSOCIATED WITH BPH.

INTRODUCTION AND OBJECTIVES: The phosphodiesterase (PDE) 5 inhibitor tadalafil is available for treatment of male lower urinary tract symptoms, while the role of other PDE isoforms for prostate smooth muscle tone is still unknown. Here, we examined effects of the PDE7-selective inhibitor BRL 50481, and the PDE10-selective inhibitor TC-E 5005 on smooth muscle contraction in the hyperplastic human prostate. METHODS: Prostate samples were obtained from patients (n1⁄495) undergoing radical prostatectomy. Expression of PDE isoforms was addressed by RT-PCR, Western blot, and immunofluorescence. Effects of TC-E 5005, BRL 50481, and tadalafil on contractility of prostate strips were studied in an organ bath. RESULTS: PDE7A1/2 and PDE10A were detectable by RTPCR, Western blot, and fluorescence staining. Colocalization with calponin and tyrosine hydroxylase suggested expression of PDE7A1/2 and PDE10A in smooth muscle cells and catecholaminergic nerves. Noradrenaline, the a1-adrenergic agonist phenylephrine, the thromboxane A2 analogue U46619, and endothelins 1-3 induced concentration-dependent contractions of prostate strips, while electric field stimulation (EFS) induced frequence-dependent contractions. Application of TC-E 5005 (500 nM) caused significant inhibition of noradrenaline-, phenylephrine-, and endothelin-3-induced contractions. Similarly, TC-E 5005 caused significant inhibiton of EFS-induced contractions. Inhibition of EFS-induced contraction by TC-E 5005 amounted to approximately 50 %, resembling inhibition of EFS-induced contraction by tadalafil (10 mM) (also around 50 %) (see figure). EFSand norepinephrine-induced tension were similar after application of tadalafil, and after combined application of tadalafil and TC-E 5005. BRL 50481 was without effect on noradrenaline-induced contraction. CONCLUSIONS: The PDE10-selective inhibitor TC-E 5005 inhibits neurogenic, adrenergic, and endothelin-3-induced smooth muscle contractions in the hyperplastic human prostate. TC-E 5005 inhibits neurogenic contractions with an efficacy similar to tadalafil. Urodynamic effects in vivo appear possible.