Additive effect of oral LDD175 to tamsulosin and finasteride in a benign prostate hyperplasia rat model

Abstract

Objective: We investigated the benefits of the BK_Ca agonist 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175) combined with tamsulosin and finasteride, in a benign prostatic hyperplasia (BPH) rat model.

Materials and methods: Castration was performed by bilateral orchiectomy under ketamine anesthesia. A rat model of BPH was established by daily intramuscular administration of testosterone propionate plus 17β-estradiol for 8 weeks. Model rats were administered combinations of 20 mg/kg LDD175, 0.01 mg/kg tamsulosin and 1 mg/kg finasteride once daily by oral gavage for 4 weeks from week 6 to 9 post-surgery. Intraurethral pressure induced by electrostimulation of the hypogastric nerve was measured at the end of administration. Body and genitourinary organ weights were recorded, serums were assayed for hormone concentrations, and tissues were subjected to histopathology, and analyses of α1-adrenoceptor mRNA and protein expression levels after treatment.

Results: Combined LDD175, tamsulosin, and finasteride significantly decreased prostatic index, serum hormone levels, epithelial thickness, and prostate expression of α1-adrenoceptors in BPH model rats. The 3-drug combination was more effective than any other combination or LDD175 alone.

Conclusion: These results suggest that LDD175 addition to tamsulosin and finasteride may be beneficial for the treatment of BPH patients who do not respond to tamsulosin plus finasteride.

Keywords: 5α-reductase inhibitors; benzofuroindole; intraurethral pressure; α1-adrenergic receptor antagonists; α1-adrenoceptors.

Figure 1

Effects of LDD175, tamsulosin, and finasteride combinations on serum hormone levels in each treatment group. Notes: (A) DHT. (B) Testosterone. (C) Free testosterone. (D) Estradiol. Values with different superscript alphabets in the same row are significantly different (P<0.05) by one-way analysis of variance and the Duncan’s multiple range tests. Abbreviations: BPH, benign prostatic hyperplasia; DHT, dihydrotestosterone; BPH+Vehicle, disease control; BPH+L, LDD175 (20 mg/kg); BPH+LT, LDD175 and tamsulosin (0.01 mg/kg); BPH+LF, LDD175 and finasteride (1 mg/kg); BPH+LTF, LDD175, tamsulosin, and finasteride; CAS+Vehicle, castration; CON+Vehicle, control.

Figure 2

Effects of LDD175, tamsulosin, and finasteride combinations on prostate histopathology and IUP response to EST of the hypogastric nerve. Notes: (A) Histological changes in the prostate. Original magnifications 20×. (B) Epithelial thickness of the prostate. (C) Effects on the IUP response to EST. (D) Effect on blood pressure (BP). Values with different superscript alphabets in the same row are significantly different (P<0.05) by one-way analysis of variance and the Duncan’s multiple range tests. Abbreviations: BPH, benign prostatic hyperplasia; BPH+Vehicle, disease control; BPH+L, LDD175 (20 mg/kg); BPH+LT, LDD175 and tamsulosin (0.01 mg/kg); BPH+LF, LDD175 and finasteride (1 mg/kg); BPH+LTF, LDD175, tamsulosin, and finasteride; CAS+Vehicle, castration; CON+Vehicle, control; EST, electrostimulation; IUP, intraurethral pressure.

Figure 3

Effects of LDD175, tamsulosin and finasteride combinations on α1-adrenoceptor subtype mRNAs and proteins expression in each treatment group as measured by real-time polymerase chain reaction and Western blotting. Notes: (A) α1A-adrenoceptor mRNA expression. (B) α1D-adrenoceptor mRNA expression. (C) α1A-adrenoceptor protein expression. (D) α1D-adrenoceptor protein expression. Values with different superscript alphabets in the same row are significantly different (P<0.05) by one-way analysis of variance and the Duncan’s multiple range tests. Abbreviations: BPH, benign prostatic hyperplasia; BPH+Vehicle, disease control; BPH+L, LDD175 (20 mg/kg); BPH+LT, LDD175 and tamsulosin (0.01 mg/kg); BPH+LF, LDD175 and finasteride (1 mg/kg); BPH+LTF, LDD175, tamsulosin, and finasteride; CAS+Vehicle, castration; CON+Vehicle, control.