Protective effect of hydroxyfasudil, a Rho kinase inhibitor, on ventral prostatic hyperplasia in the spontaneously hypertensive rat.
BACKGROUND
Rho kinase (ROCK) pathway is associated with various cellular functions, such as smooth muscle contraction, inflammatory response, and cell proliferation. The spontaneously hypertensive rat (SHR) is commonly used genetically hypertensive rat model which develops hyperplastic morphological abnormalities in the ventral prostate. We investigated whether administration of hydroxyfasudil, a ROCK inhibitor, could reduce the levels of growth factors, inflammatory markers, and morphological abnormalities in the ventral prostate of the SHR.


METHODS
Twelve-week-old SHRs were treated with hydroxyfasudil (1 mg/kg/day, i.p.) or vehicle once daily for another 6 weeks. Wistar Kyoto (WKY) rats treated with vehicle were used as normotensive controls. At 18 weeks of age, blood pressure and heart rate were measured by the tail cuff method. Then the rats were sacrificed, and the ventral prostates were removed. The levels of ROCK activity, growth factors (TGF-β1 and bFGF), a smooth muscle differentiation marker (α-SMA) and an inflammatory cytokine (IL-6) in the ventral prostate were measured by ELISA and western blot. A histological evaluation in each group was also performed.


RESULTS
There were significant increases in blood pressure, prostate weight, prostate body weight ratio, and tissue levels of ROCK activity, TGF-β1, bFGF, α-SMA, and IL-6 in the SHR compared to the WKY rat. Histological examination of the ventral prostate showed morphological abnormalities such as a higher degree of proliferation in the glandular epithelial and stromal area in the SHR compared to the WKY rat. Treatment with hydroxyfasudil reduced the elevated ROCK activity, TGF-β1, bFGF, α-SMA, and IL-6 found in the ventral prostate of the SHR. Moreover, treatment with hydroxyfasudil decreased the morphological abnormalies in the SHR ventral prostate.


CONCLUSIONS
Treatment with hydroxyfasudil decreased the growth factors, an inflammatory cytokine, and morphological abnormalies in the SHR ventral prostate. These results suggest that chronic treatment with hydroxyfasudil may inhibit the progression of prostatic hyperplasia in the SHR.
Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
Felix
F
Holmström
Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
Shogo
S
Shimizu
Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
Takahiro
T
Shimizu
Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
Youichirou
Y
Higashi
Department of Urology, Yale University School of Medicine, New Haven, Connecticut.
Darryl T
DT
Martin
Department of Surgery, Division of Urology, Tottori University School of Medicine, Yonago, Japan.
Masashi
M
Honda
Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
Motoaki
M
Saito
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases
growth factor; hydroxyfasudil; prostate; spontaneously hypertensive rat