Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide
Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide
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DOI：
10.1152/ajpheart.01101.2009
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发表时间：
2010-10-01
影响因子：
4.8
通讯作者：
Kadowitz, Philip J.
中科院分区：
文献类型：
--
作者：
Badejo, Adeleke M., Jr.;Nossaman, Vaughn E.;Kadowitz, Philip J.
Badejo AM Jr，Nossaman VE，Pankey EA，Bhartiya M，Kannadka CB，Murthy SN，Nossaman BD，Kadowitz PJ。肺和全身血管扩张剂对可溶性鸟苷酸环化酶激动剂Bay 41-8543的反应受一氧化氮的调节。Am J Physiol心圈Physiol 299：H1153-H1159,2010。2010年7月16日首次出版；doi：10.1152/ajpheart.01101.2009.-Bay 41-8543是一种不依赖一氧化氮(NO)的可溶性鸟苷酸环化酶(SGC)刺激物。在基础和高张力条件下，以及N-omega-硝基-L-精氨酸甲酯(L-NAME)抑制一氧化氮合酶(NOS)时，观察静脉注射BAY 41-8543的反应。在基线条件下，静脉注射Bay 41-8543导致肺动脉压轻微下降，全身动脉压下降较大，心输出量增加。静脉注射U-46619使肺动脉压升高至接近30毫米汞柱时，静脉注射BAY41-8543可引起较大的剂量依赖性的肺动脉压下降，而对SGC刺激剂所致的肺动脉压和体动脉压的相对下降幅度相似。在U-46619和U-46619+L-NAME处理的动物中，当肺动脉压升高到类似值(接近30毫米汞)时，用L-NAME明显降低对BAY 41-8543的反应。静脉注射小剂量硝普钠(SNP)与BeAY 41-8543联合应用可增强L处理的动物对SGC刺激剂的肺和全身血管扩张反应。结果表明，当U-46619增强肺血管收缩张力时，BAY41-8543在体循环和肺血管床上具有相似的血管扩张活性。这些结果表明，当一氧化氮合酶被L-NAME抑制时，对BAY 41-8543的肺和全身血管扩张反应明显减弱，而在L-NAME处理的动物中，与小剂量硝普钠合用则增强对BAY 41-8543的血管扩张反应。本结果与肺和全身血管扩张对sGC刺激剂的反应不独立的观点一致，然而，当内源性NO的产生被L-NAME抑制时，该化合物的血管扩张活性显著降低。这些数据表明，Bay 41-8543在大鼠肺血管床和全身血管床上具有相似的血管扩张活性。
Badejo AM Jr, Nossaman VE, Pankey EA, Bhartiya M, Kannadka CB, Murthy SN, Nossaman BD, Kadowitz PJ. Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide. Am J Physiol Heart Circ Physiol 299: H1153-H1159, 2010. First published July 16, 2010; doi:10.1152/ajpheart.01101.2009.-BAY 41-8543 is a nitric oxide (NO)-independent stimulator of soluble guanylyl cyclase (sGC). Responses to intravenous injections of BAY 41-8543 were investigated under baseline and elevated tone conditions and when NO synthase (NOS) was inhibited with N-omega-nitro-L-arginine methyl ester (L-NAME). Under baseline conditions, intravenous injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to similar to 30 mmHg with an intravenous infusion of U-46619, intravenous injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with L-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (similar to 30 mmHg) in U-46619-infused and in U-46619-infused plus L-NAME-treated animals. The intravenous injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in L-NAME-treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U-46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by L-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in L-NAME-treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent; however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with L-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat.