Y-27632, a Rho-kinase inhibitor, inhibits proliferation and adrenergic contraction of prostatic smooth muscle cells.
OBJECTIVE
Benign prostatic hyperplasia (BPH) causes mechanical urinary flow obstruction by 2 components, namely an enlarged prostate (static component) and elevated smooth muscle tone (dynamic component). Currently available treatments for BPH aim to inhibit the proliferation of prostatic cells or decrease the elevated tone. To our knowledge no single agent that can achieve these 2 ends has yet been identified. A specific inhibitor of Rho-kinase, Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride), has been demonstrated to cause smooth muscle relaxation and inhibit smooth muscle cell proliferation. Therefore, we investigated the effect of Y-27632 on prostatic smooth muscle proliferation and tone.


METHODS
Rho-kinase expression was investigated by immunocytochemistry and immunoblotting in smooth muscle cells obtained from rat and human prostates. The effect of Y-27632 was examined on the proliferation of these cells and on the contractions elicited by electrical field stimulation and exogenous phenylephrine in rat prostatic strips.


RESULTS
Immunoblot and immunofluorescence analysis showed that Rho-kinase is present in the cytosol and located in the perinuclear region in human and rat prostatic smooth muscle cells. Y-27632 decreased the proliferation of human and rat prostatic smooth muscle cells, and inhibited noradrenergic contractions elicited by electrical field stimulation and exogenous phenylephrine in rat prostatic strips (EC50 17.8 +/- 4.8 and 7.8 +/- 2.1 microM, respectively).


CONCLUSIONS
To our knowledge we report the first demonstration of the presence of Rho-kinase in prostatic smooth muscle cells, and of the relaxant and antiproliferative effect of a Rho-kinase inhibitor. We suggest a novel use for Rho-kinase inhibitors in the treatment of BPH as a single agent with dual action.
Rees
Rowland W
RW
Wolfson Institute for Biomedical Research, University College London, United Kingdom.
Foxwell
Neale A
NA
Ralph
David J
DJ
Kell
Phil D
PD
Moncada
Salvador
S
Cellek
Selim
S
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases
D000316:Adrenergic alpha-Agonists; D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009638:Norepinephrine