Drug Discovery Research, Astellas Pharma Inc., Japan.
Drug Discovery Research, Astellas Pharma Inc., Japan.
Eur J Pharmacol. 2019 Jun 15;853:11-17. doi: 10.1016/j.ejphar.2019.03.011. Epub 2019 Mar 7.
Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA) receptor, suggesting the potential of the LPA receptor as a therapeutic target. However, the role of LPA and the LPA receptor in bladder function has not been studied in vivo. We investigated the effects of LPA and the novel LPA receptor antagonist ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}- 1,3-thiazole-4-carbonyl)- 3-ethyl-2,2-dioxo-2λ-diazathian-1-ide) on the micturition reflex in conscious rats using cystometry. Intravenous infusion of LPA decreased the micturition interval and threshold pressure with no apparent changes in baseline pressure or maximum intravesical pressure. ASP6432 inhibited the LPA-induced decrease in MI. In contrast, ASP6432 had no effect on the LPA-induced decrease in threshold pressure. Similarly, ASP6432 had no effect on either baseline pressure or maximum intravesical pressure. We also evaluated the effect of ASP6432 on the urinary frequency induced by the nitric oxide synthase inhibitor L-N-nitro arginine methyl ester (L-NAME). Intravenous L-NAME administration decreased the micturition interval. ASP6432 dose-dependently reversed the L-NAME-induced decrease in micturition interval. Our findings demonstrate for the first time that LPA causes bladder overactivity in rats. ASP6432 inhibited the LPA- and L-NAME-induced decrease in micturition interval, suggesting a significant role for the LPA receptor in regulating the functional capacity of the bladder. Our results also suggest the potential of ASP6432 as a novel therapy for the treatment of bladder dysfunction associated with lower urinary tract diseases.
良性前列腺增生相关的膀胱功能障碍不能被当前的药物治疗充分缓解。溶血磷脂酸（LPA）是一种具有多种生物学效应的磷脂。LPA 通过 1 型 LPA（LPA）受体调节前列腺和尿道收缩，表明 LPA 受体作为治疗靶点的潜力。然而，LPA 和 LPA 受体在膀胱功能中的作用尚未在体内进行研究。我们使用膀胱测压法研究了 LPA 和新型 LPA 受体拮抗剂 ASP6432（potassium 1-（2- {[3,5-dimethoxy-4-methyl-N-（3-phenylpropyl）benzamido]methyl} -1,3-thiazole-4-carbonyl）-3-ethyl-2,2-dioxo-2λ-diazathian-1-ide）对清醒大鼠排尿反射的影响。静脉内输注 LPA 可减少排尿间隔和阈值压力，而基线压力或最大膀胱内压力无明显变化。ASP6432 抑制了 LPA 引起的 MI 降低。相反，ASP6432 对 LPA 引起的阈值压力降低没有影响。同样，ASP6432 对基线压力或最大膀胱内压力也没有影响。我们还评估了 ASP6432 对一氧化氮合酶抑制剂 L-N-硝基精氨酸甲酯（L-NAME）引起的尿频率的影响。静脉内给予 L-NAME 可减少排尿间隔。ASP6432 剂量依赖性地逆转了 L-NAME 引起的排尿间隔减少。我们的研究结果首次证明 LPA 可导致大鼠膀胱过度活动。ASP6432 抑制了 LPA 和 L-NAME 引起的排尿间隔减少，表明 LPA 受体在调节膀胱功能容量方面具有重要作用。我们的研究结果还表明，ASP6432 作为治疗下尿路疾病相关膀胱功能障碍的新型治疗方法具有潜力。
