Suzuki Y, Kanada A, Okaya Y, Aisaka K, Muramatsu I
Central Pharmacological Research Institute, Japan Tobacco, Takatsuki, Osaka.
Eur J Pharmacol. 1999 Jun 25;374(3):495-502. doi: 10.1016/s0014-2999(99)00344-1.
In the present study, we investigated the effect of JTH-601 (3-{N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminomethyl}-4-methoxy-2,5,6-trimethylphenol hemifumarate), a novel alpha1-adrenoceptor antagonist, in vitro and in vivo. JTH-601 (10(-9)-3 x 10(-8) M) competitively antagonized phenylephrine-induced contraction in lower urinary tract tissues (prostate, urethra and bladder trigon) in a concentration-dependent manner. The mean pA2 values for JTH-601 were 8.59+/-0.14, 8.74+/-0.09 and 8.77+/-0.11 for prostate, urethra and bladder trigon, respectively. In anesthetized rabbits, intraduodenal administration of JTH-601 (0.3-3 mg/kg), prazosin (0.03-0.3 mg/kg) and tamsulosin (0.03-0.3 mg/kg) dose dependently inhibited the phenylephrine-induced increase in urethral pressure for 3 h. Although these drugs also decreased mean blood pressure, JTH-601 was less potent than prazosin or tamsulosin. In conscious rabbits, administered JTH-601 (0.01-1 mg/kg, i.v.) had a tendency to augment orthostatic hypotension, but dose dependency was not evident. Prazosin (0.01-1 mg/kg) and tamsulosin (0.001-1 mg/kg) dose dependently augmented orthostatic hypotension. These results indicate that JTH-601 antagonized alpha1-adrenoceptor-mediated contractile responses more potently than prazosin or tamsulosin in rabbit lower urinary tract both in vitro and in vivo. JTH-601 is therefore expected to be effective in the treatment of urinary outlet obstruction in benign prostatic hypertrophy.
在本研究中，我们研究了新型α1肾上腺素能受体拮抗剂JTH - 601（3 - {N - [2 - (4 - 羟基 - 2 - 异丙基 - 5 - 甲基苯氧基)乙基]-N - 甲基氨基甲基}-4 - 甲氧基 - 2,5,6 - 三甲基苯酚半富马酸盐）在体外和体内的作用。JTH - 601（10^(-9) - 3×10^(-8) M）以浓度依赖性方式竞争性拮抗去氧肾上腺素诱导的下尿路组织（前列腺、尿道和膀胱三角区）收缩。JTH - 601对前列腺、尿道和膀胱三角区的平均pA2值分别为8.59±0.14、8.74±0.09和8.77±0.11。在麻醉兔中，十二指肠内给予JTH - 601（0.3 - 3 mg/kg）、哌唑嗪（0.03 - 0.3 mg/kg）和坦索罗辛（0.03 - 0.3 mg/kg）剂量依赖性地抑制去氧肾上腺素诱导的尿道压力升高达3小时。虽然这些药物也降低平均血压，但JTH - 601的效力低于哌唑嗪或坦索罗辛。在清醒兔中，静脉注射JTH - 601（0.01 - 1 mg/kg）有增强体位性低血压的趋势，但剂量依赖性不明显。哌唑嗪（0.01 - 1 mg/kg）和坦索罗辛（0.001 - 1 mg/kg）剂量依赖性地增强体位性低血压。这些结果表明，在体外和体内，JTH - 601在兔下尿路中比哌唑嗪或坦索罗辛更有效地拮抗α1肾上腺素能受体介导的收缩反应。因此，JTH - 601有望有效治疗良性前列腺增生引起的尿路梗阻。
