1 This study was intended to quantify the amounts of the a 1 -adrenoceptor subtype mRNAs in human vas deferens, and demonstrate the receptor subtype responsible for the vas contraction. 2 The RNase protection assay showed that the mean total amount of a 1a mRNA was 7.4+2.2 pg/5 mg of poly (A) + RNA (97.0% of the total a 1 mRNA) in the epididymal portion (E-vas) and 4.9+0.8 pg/ 5 mg of poly (A) + RNA (96.3% of the total) in the pelvic portion (P-vas). The E-vas showed a tendency to have a greater a 1a mRNA abundance than the P-vas (P=0.11). The a 1b and a 1d mRNAs were absent or of extremely low abundance.3 By an in situ hybridization, the a 1a and a 1d mRNAs were recognized in the smooth muscle cells of the E-vas and the P-vas, and the distribution pattern the same in both tissues. The a 1b mRNA positive site was scarcely detectable in both vas portions. 4 In a functional study, l-phenylephrine produced concentration-dependent contraction in the E-vas (E max =2.24+0.70 g; pD 2 =5.32+0.09) and the P-vas (E max =2.46+0.46 g; pD 2 =5.07+0.12). KMD-3213, a novel a 1A -adrenoceptor-selective antagonist, caused parallel rightward shifts of the concentration ± response curves for l-phenylephrine. Apparent pK B values were 9.90+0.16 for the Evas and 9.71+0.17 for the P-vas. There was no signi®cant di erence in E max , pD 2 or pK B estimates between the two portions. 5 We have found that a 1a mRNA is predominant in the human vas deferens, and con®rmed that contraction of this organ is mediated by the a 1A -adrenoceptor.

These results suggest that KMD-3213 is a substantially prostate-selective alpha 1-AR antagonist in human tissues compared with other alpha 1-AR antagonists.

These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.

No abstract

Background: KMD-3213 is an a 1A -adrenoceptor-selective antagonist currently being developed for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia. In the present study, the uroselectivity of KMD-3213 was evaluated and compared with that of prazosin and tamsulosin in a decerebrate dog model. Methods: Intercollicular decerebration was carried out in male mongrel dogs under anesthesia. The inhibitory effects of intravenously and intraduodenally administered compounds on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve were estimated. Systemic blood pressure was measured simultaneously. Results:The a 1 -antagonists tested produced a dose-dependent inhibition of the induced IUP response and decreased mean blood pressure (MBP). The ID 50 of KMD-3213, tamsulosin and prazosin for IUP (dose required to inhibit the increase in IUP by 50%) was 3.15, 1.73 and 11.8 mg/kg i.v., respectively, and the ED 20 for the hypotensive effect (dose required to reduce MBP by 20%) was 8.03, 0.59 and 2.46 mg/kg i.v., respectively. The data indicate that uroselectivity (ED 20 /ID 50 ) of KMD-3213 is 12-and 7.5-fold higher than that of prazosin and tamsulosin, respectively. When the drugs were administered intraduodenally, KMD-3213 was sufficiently absorbed from the digestive tract and continued to demonstrate at least 3.8-fold higher uroselectivity than tamsulosin. Conclusion: Based on these findings, KMD-3213 appears to be an effective orally active compound for decreasing urethral resistance during micturition that does not induce any negative cardiovascular effects in patients with benign prostatic hyperplasia.