Suzuki Y, Kanada A, Okaya Y, Kurahashi Y, Kogayu M, Kobayashi T, Aisaka K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
BJU Int. 2000 Mar;85(4):542-50. doi: 10.1046/j.1464-410x.2000.00443.x.
To evaluate the effect of JTH-601-G1, an active metabolite and glucuronide conjugate of JTH-601 (an alpha1-adrenoceptor antagonist), on smooth muscle contraction in canine prostate and artery, and to examine the effect of JTH-601-G1 on prostatic urethral pressure and blood pressure in anaesthetized dogs. Materials and methods Male beagle dogs were used in both an in vitro and an in vivo study. In the former, the prostate and right common carotid artery were isolated, and smooth muscle strips from the prostate and open-ring strips from the carotid artery prepared. The effects of JTH-601-G1 on phenylephrine- and noradrenaline-induced contraction were assessed in these tissues. In the in vivo study, four dogs were anaesthetized and the change in urethral pressure, blood pressure and heart rate measured continuously. Vehicle (saline) and JTH-601-G1 were then infused intravenously in increasing doses (0.33-3.3 microg/kg/min for 30 min). In three other dogs, the effect of JTH-601-G1 infusion at a higher rate (25 microg/kg/min for 3 h) on blood pressure was evaluated, and the plasma concentration of JTH-601-G1 measured using high-performance liquid chromatography-mass spectrometry.
Of the distinct metabolites of JTH-601, JTH-601-G1 had the most potent alpha1-adrenoceptor antagonistic effect in isolated canine prostate. JTH-601-G1 also antagonized alpha1-adrenoceptor agonist-induced contraction in common carotid artery, but the pA2 value in the artery was approximately 25 times higher than that in the prostate. In anaesthetized dogs, JTH-601-G1 decreased urethral pressure in a dose-dependent manner; at the highest dose, urethral pressure decreased by 24.5% and blood pressure by 7.0%. However, there was no significant change in heart rate at any dose. The plasma concentration of JTH-601-G1 increased with the dose of JTH-601-G1, but the concentration of both JTH-601 and other metabolites was below the detection limit. The higher JTH-601-G1 infusion rate caused blood pressure to decrease by only 6-10% even at JTH-601-G1 plasma concentrations of approximately 1500 ng/mL during the infusion. Although there was a negative correlation between mean blood pressure and plasma JTH-601-G1 concentration, the decrease in blood pressure was small compared with the reduction in urethral pressure.
JTH-601-G1 appears to be a major active metabolite of JTH-601 but with a higher selectivity for canine prostate than artery. The results also indicate that in addition to the alpha1A-adrenoceptor, the alpha1L-adrenoceptor plays an important prostatic selective role in smooth muscle contraction via the alpha1-adrenoceptor.
评估JTH - 601的活性代谢产物及葡糖醛酸共轭物JTH - 601 - G1（一种α1 - 肾上腺素能受体拮抗剂）对犬前列腺和动脉平滑肌收缩的影响，并研究JTH - 601 - G1对麻醉犬前列腺尿道压力和血压的作用。材料与方法雄性比格犬用于体外和体内研究。在体外研究中，分离前列腺和右颈总动脉，制备前列腺平滑肌条和颈动脉开口环条。评估JTH - 601 - G1对苯肾上腺素和去甲肾上腺素诱导的这些组织收缩的影响。在体内研究中，麻醉4只犬，连续测量尿道压力、血压和心率的变化。然后以递增剂量（0.33 - 3.3微克/千克/分钟，持续30分钟）静脉输注溶媒（生理盐水）和JTH - 601 - G1。在另外3只犬中，评估以较高速率（25微克/千克/分钟，持续3小时）输注JTH - 601 - G1对血压的影响，并使用高效液相色谱 - 质谱法测量JTH - 601 - G1的血浆浓度。
在JTH - 601的不同代谢产物中，JTH - 601 - G1在分离的犬前列腺中具有最有效的α1 - 肾上腺素能受体拮抗作用。JTH - 601 - G1也拮抗α1 - 肾上腺素能受体激动剂诱导的颈总动脉收缩，但动脉中的pA2值比前列腺中的高约25倍。在麻醉犬中，JTH - 601 - G1以剂量依赖方式降低尿道压力；在最高剂量时，尿道压力降低24.5%，血压降低7.0%。然而，在任何剂量下心率均无显著变化。JTH - 601 - G1的血浆浓度随JTH - 601 - G1剂量增加而升高，但JTH - 601和其他代谢产物的浓度均低于检测限。即使在输注期间JTH - 601 - G1血浆浓度约为1500纳克/毫升时，较高的JTH - 601 - G1输注速率也仅使血压降低6 - 10%。尽管平均血压与血浆JTH - 601 - G1浓度之间存在负相关，但与尿道压力降低相比，血压降低幅度较小。
JTH - 601 - G1似乎是JTH - 601的主要活性代谢产物，但对犬前列腺的选择性高于动脉。结果还表明，除α1A - 肾上腺素能受体外，α1L - 肾上腺素能受体在通过α1 - 肾上腺素能受体的平滑肌收缩中起重要的前列腺选择性作用。
