Keeble J, Al-Swayeh O A, Moore P K
Messengers and Signalling Group, School of Biomedical Sciences, King's College London, Hodgkin Building, Guy's Campus, London SE1 9RT, UK.
Br J Pharmacol. 2001 Aug;133(7):1023-8. doi: 10.1038/sj.bjp.0704161.
The effect of several nitric oxide releasing-non-steroidal anti-inflammatory drugs (NO-NSAID) and nitroprednisolone on blood vessel relaxation in vitro and in vivo was studied. Nitroflurbiprofen (NOF; EC(50), 688.8+/-93.8 microM), nitroaspirin (NOA; EC(50), 57.9+/-6.5 microM), nitroparacetamol (NOPARA; EC(50), 71.5+/-14.6 microM) and nitroprednisolone (EC(50), 15.1+/-1.4 microM) caused concentration-related relaxation of noradrenaline (NA)-contracted rat aortic rings. All NO releasing compounds tested were approximately three orders of magnitude less potent than sodium nitroprusside (SNP, EC(50), 35.7+/-3.5 nM). The vasorelaxant effect of NOF and NOPARA in the rat aorta was potentiated by zaprinast (5 microM) and reduced by ODQ (5 microM). Flurbiprofen and paracetamol (100 microM) caused minimal (<10%) relaxation of the rat aorta and did not affect the response to SNP. The effect of NOF was unchanged in the presence of L-NAME (100 microM; EC(30), 181.8+/-35.1 microM cf. EC(30), 125.1+/-17.0 microM, P>0.05) but increased by removal of the endothelium (EC(30), 164.3+/-26.3 microM cf. EC(50), 688.8+/-93.8 microM, P<0.05). NOF (0.1 - 50 microM) produced a small but not concentration-related vasodilation of the NA-preconstricted (i.e. "high tone") perfused rat mesentery preparation (cf. SNP, EC(30), 4.4+/-0.7 microM). In contrast, NOF (1 - 100 microM) produced concentration-related vasodilation of the "high tone" perfused rat kidney with an EC(50) of 33.1+/-4.4 microM. Neither NOF (74 mg kg(-1), i.p.) nor NOA (91.9 mg kg(-1), i.p.) nor equimolar doses of flurbiprofen (50 mg kg(-1), i.p.) or aspirin (50 mg kg(-1), i.p.) affected mean arterial blood pressure (MAP) or heart rate (HR) of pentobarbitone-anaesthetized rats over a 1 h period. NO-NSAID relax blood vessels in vitro by an NO-dependent mechanism. The absolute vasorelaxant effect of NO releasing drug varies greatly with the choice of compound and between blood vessel preparations.
研究了几种释放一氧化氮的非甾体抗炎药（NO-NSAID）和硝基泼尼松龙对体外和体内血管舒张的作用。氟比洛芬硝基酯（NOF；半数有效浓度（EC50），688.8±93.8微摩尔）、阿司匹林硝基酯（NOA；EC50，57.9±6.5微摩尔）、对乙酰氨基酚硝基酯（NOPARA；EC50，71.5±14.6微摩尔）和硝基泼尼松龙（EC50，15.1±1.4微摩尔）可引起去甲肾上腺素（NA）收缩的大鼠主动脉环呈浓度依赖性舒张。所有测试的释放NO的化合物的效力比硝普钠（SNP，EC50，35.7±3.5纳摩尔）弱约三个数量级。扎普司特（5微摩尔）可增强NOF和NOPARA在大鼠主动脉中的血管舒张作用，而1H-[1,2,4]恶唑并[4,3-a]喹啉-1-酮（ODQ，5微摩尔）可减弱该作用。氟比洛芬和对乙酰氨基酚（100微摩尔）引起大鼠主动脉最小程度的（<10%）舒张，且不影响对SNP的反应。在L-NAME（100微摩尔；30%有效浓度（EC30），181.8±35.1微摩尔，对比EC30，125.1±17.0微摩尔，P>0.05）存在的情况下，NOF的作用未改变，但去除内皮后作用增强（EC30，164.3±26.3微摩尔，对比EC50，688.8±93.8微摩尔，P<0.05）。NOF（0.1 - 50微摩尔）对NA预收缩（即“高张力”）的灌注大鼠肠系膜制备物产生小幅度但与浓度无关的血管舒张作用（对比SNP，EC30，4.4±0.7微摩尔）。相反，NOF（1 - 100微摩尔）对“高张力”灌注的大鼠肾脏产生浓度依赖性血管舒张作用，EC50为33.1±4.4微摩尔。在1小时内，NOF（74毫克/千克，腹腔注射）、NOA（91.9毫克/千克，腹腔注射）或等摩尔剂量的氟比洛芬（50毫克/千克，腹腔注射）或阿司匹林（50毫克/千克，腹腔注射）均未影响戊巴比妥麻醉大鼠的平均动脉血压（MAP）或心率（HR）。NO-NSAID通过NO依赖性机制在体外使血管舒张。释放NO药物的绝对血管舒张作用因化合物的选择以及血管制备物的不同而有很大差异。
