Characterization of prostatic alpha-l adrenoceptors in human benign prostatic hypertrophy.

• Project/Area Number: 03671102
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: 応用薬理学・医療系薬学
• Research Institution: School of Pharmaceutical Sciences, University of Shizuoka
• Principal Investigator: YAMADA Shizuo School of Pharmaceutical Sciences University of Shizuoka Department of Biopharmacy Associate Professor, 薬学部, 助教授 (80106434)
• Project Period (FY): 1991 – 1992
• Project Status: Completed (Fiscal Year 1992)
• Budget Amount: ¥2,100,000 (Direct Cost: ¥2,100,000); Fiscal Year 1992: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 1991: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: Human prostate / Alpha_l adrenoceptors / Radioreceptor assay / [^3H] prazosin / [^3H] bunazosin / Alpha_l antagonists / Human aorta / Alpha_l adrenoceptor subtype / 前立腺肥大症 / 前立腺 / α_1-レセプター / 〔^3H〕プラゾシン / レセプター結合動態 / α_1^-レセプタ- / ラジオレセプタ-アッセイ / α_1^-拮抗薬 / レセプタ-結合動態

Research Abstract

To identify and charaterize alpha-1 adrenoceptors in human prostates, specific binding of [^3H] prazosin and [^3H] bunazosin in crude prostatic membranes from patients with benign prostatic hypertrophy (BPH) was measured. Specific binding of [^3H] prazosin and [^3H] bunazosin was saturable, reversible and of high affinity (Kd values=0.35 nM and 1.03 nM, respectively), and it showed a pharmacological specificity as well as stereoselectivity which characterized alpha-1 adrenoceptors. Alpha-1 antagonists competed with both radioligands for the binding sites in human prostates in order : YM617 > prazosin > bunazosin > terazosin > naftopidil > urapidil. The potencies (pKi) of alpha-1 antagonists in competing for the radioligand binding sites in human prostates correlated well with their pharmacological potencies (pA_2) in the prostates. Scatchard analysis indicated that the decrease of prostatic [^3H] prazosin binding by prazosin, bunazosin and naftopidil was due to a significant in-crease in the Kd value without a change in the Bmax value. Also, the inhibitory effect of specific [^3H] prazosin binding by prazosin was identical in human prostate and aorta, but that by YM617 was approximately 14 times more potent in human prostate than in the aorta. Chlorethylclonidine treatment inhibited partially specific [^3H] prazosin binding in both tissues, thereby suggesting the coexistence of alpha-1 adrenoceptor subtypes (alpha-la and alpha-1b).
There was a significant increase in the maximal number of binding sites for [^3H] prazosin and [^3H] bunazosin in hypertrophied prostates from BPH compared to normal tissues without BPH, whereas BPH had little effect on the dissociation constants for both radioligands. Also, there was a regional variation of alpha-1 adrenoceptor binding sites in the human prostate in order : inner zone > outer zone > prostatic urethra.
Thus, we conclude : 1) [^3H] prazosin and [^3H] bunazosin selectively labels alpha-1 adrenoceptors in human prostates, 2) alpha-1 antagonists such as YM617 and prazosin antagonizes alpha-1 adrenoceptors (in a competitive and reversible manner) with high affinity, 3) YM617 is relatively selective antagonist of alpha-1 adrenoceptors in human prostate than in human aorta and 4) there is a greater density of alpha-1 adrenoceptor sites in BPH.

Research Products

• [Publications] Yamada,S.,Suzuki,M.,Matsuoka,Y.,Kato,Y.,Kimura,R.,Maruyama,M.,Kawabe,K.: "[ ^3]Bunazosin,a novel selective radioligand of alpha¬ adrenoceptors in human prostate" Journal of Urology. 146. 877-880 (1991)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yamada,S.,Suzuki,M.,Kato,Y.,Kimura,R.,Mori,R.,Matsumoto,K.,Maruyama,M.,Kawabe,K.: "Binding characteristics of naftopidil and alpha¬-adrenoceptor antagonists to prostatic alpha-adrenoceptors in benign prostatic hypertrophy" Life Sciences. 50. 127-135 (1992)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yamada, S., Suzuki, M., Matsuoka, Y., Kato, Y., Kimura, R., Maruyama, M., and Kawade, K.: "[^3H] Bunazosin, a novel selective radioligand of alpha_l adrenoceptors in human prostate" J.Urol.146. 877-880 (1991)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamada, S., Suzuki, M., Kato, Y., Kimura, R., Mori, R., Matsumoto, K., Mayuyama, M., and Kawade, K.: "Binding characteristics of naftopidil and alpha_*-adrenoceptor antagonists to prostatic alpha-adrenoceptors in benign prostatic hypertrophy" Life Sci.50. 127-135 (1992)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamada,S.,Suzuki,M.,Kato,Y.,Kimura,R.et al.: "Binding characteristics of naftopidil and alpha-adrenoceptor antagonists to prostatic alpha-adrenoceptors in benign prostatic hypertrophy" Life Sciences. 50. 127-135 (1992)
• [Publications] Yamada,S.,Suzuki,M.,Matsuoka,Y.,Kato,Y.,Kimura,R.,Maruyama,M.& Kawabe,K.: "[ ^3H]Bunazosin,a novel selective radioligand of alpha_1 adrenoceptors in numan prostates" Journal of Urology. 146. 877-880 (1991)
• [Publications] Yamada,S.,Suzuki,M.,Kato,Y.,Kimura,R.,Mori,R.,Matsumoto,K.,Maruyama,M.& Kawabe,K.: "Binding characteristics of naftopidil and _l^-adrenoceptor sntagoーnists to prostatic -adrenoceptors in benign prostatic hypertrophy" Life Sciences. 50. 127-135 (1992)