Toque Haroldo A Flores, Antunes Edson, Teixeira Cleber E, De Nucci Gilberto
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
Urology. 2008 Sep;72(3):711-5. doi: 10.1016/j.urology.2007.12.031. Epub 2008 Mar 21.
To study the direct relaxant activity of 5-cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-ylamine (BAY 41-2272) in the rabbit penile urethra and to investigate its modulatory effect on nitric oxide (NO)-mediated responses.
Urothelium-intact (U+) and denuded (U-) rings were mounted in 10-mL organ baths for isometric force recording. Intracellular cyclic guanosine monophosphate (cGMP) levels were quantified with specific kits.
BAY 41-2272 (0.0001 to 10 micromol/L) caused relaxation of urethral rings contracted with phenylephrine (10 micromol/L), with higher potency (P <0.01) in U+ (pEC(50) 7.77 +/- 0.09) compared with U- (pEC(50) 6.84 +/- 0.19) preparations. The NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (100 micromol/L) or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 micromol/L) had no effect on BAY 41-2272 responses in U+ or U- rings. The phosphodiesterase-5 inhibitor vardenafil (0.1 micromol/L) potentiated the relaxant effects of BAY 41-2272 in both U+ (10-fold) and U- (sevenfold) tissues. Ca(2+)-induced contractions in K(+) depolarized rings were significantly attenuated by BAY 41-2272 (1 micromol/L) in an ODQ-insensitive manner. BAY 41-2272 (0.03-0.3 micromol/L) increased the amplitude and duration of electrical field stimulation-induced relaxations (1 to 32 Hz), as well as those evoked by the NO donor glyceryl trinitrate (0.0001 to 10 micromol/L). BAY 41-2272 induced ODQ-resistant increases in cGMP levels above baseline (approximately twofold) in both U+ and U- rings.
BAY 41-2272 relaxes penile urethra in a synergic fashion with NO. Targeting soluble guanylate cyclase with BAY 41-2272 may represent a new therapy in the management of voiding disturbances associated with impaired NO-cGMP signaling.
研究5-环丙基-2-[1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-4-胺（BAY 41-2272）对兔阴茎尿道的直接舒张活性，并探讨其对一氧化氮（NO）介导反应的调节作用。
将完整尿路上皮（U+）和去尿路上皮（U-）的尿道环安装在10 mL器官浴槽中进行等长张力记录。用特定试剂盒定量细胞内环磷酸鸟苷（cGMP）水平。
BAY 41-2272（0.0001至10 μmol/L）可使由去氧肾上腺素（10 μmol/L）引起收缩的尿道环舒张，与U-（pEC(50) 6.84±0.19）制剂相比，在U+制剂中效力更高（P<0.01）（pEC(50) 7.77±0.09）。NO合成抑制剂N(ω)-硝基-L-精氨酸甲酯（100 μmol/L）或可溶性鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮（ODQ）（10 μmol/L）对U+或U-环中BAY 41-2272的反应无影响。磷酸二酯酶5抑制剂伐地那非（0.1 μmol/L）增强了BAY 41-2272在U+（10倍）和U-（7倍）组织中的舒张作用。BAY 41-2272（1 μmol/L）以ODQ不敏感的方式显著减弱K+去极化环中Ca(2+)诱导的收缩。BAY 41-2272（0.03 - 0.3 μmol/L）增加了电场刺激（1至32 Hz）诱导的舒张幅度和持续时间，以及由NO供体硝酸甘油（0.0001至10 μmol/L）诱发的舒张幅度和持续时间。BAY 41-2272在U+和U-环中均诱导cGMP水平比基线升高（约两倍）且不受ODQ影响。
BAY 41-2272与NO协同舒张阴茎尿道。用BAY 41-2272靶向可溶性鸟苷酸环化酶可能代表一种治疗与NO-cGMP信号受损相关排尿障碍的新疗法。
