Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands;
Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H918-27. doi: 10.1152/ajpheart.00331.2013. Epub 2014 Jan 24.
Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 μg·min(-1)·kg(-1) iv) each produced coronary vasodilation at rest and during exercise as well as in preconstricted isolated coronary small arteries. In contrast, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527, both in vivo and in vitro. Importantly, EMD360527 (3 μM) and cGMP analog 8-Br-cGMP (100 μM) had no significant effects on ET-induced contractions of isolated porcine coronary small arteries, suggesting unperturbed ET receptor responsiveness. In contrast, PDE5 inhibition and cGMP blunted the contractions produced by the ET precursor Big ET, but only in vessels with intact endothelium, suggesting that PDE5 inhibition limited ET production in the endothelium of small coronary arteries. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is mediated, in part, via an increase in endothelial ET production.
一氧化氮（NO）诱导的冠状动脉舒张是通过环鸟苷酸单磷酸（cGMP）的产生和内皮素-1（ET）系统的抑制来介导的。我们之前的研究表明，磷酸二酯酶-5（PDE5）介导的 cGMP 分解和 ET 都对冠状动脉阻力血管施加了血管收缩作用。然而，对于这两种血管收缩机制对冠状动脉阻力血管张力的综合控制知之甚少。在本研究中，我们研究了 PDE5 和 ET 在体内（休息和分级跑步机运动期间）以及体外对猪冠状动脉阻力血管张力的调节作用。TEZOSENTAN（3mg/kg iv）对 ETA/ETB 受体的阻断和 EMD360527（300μg·min(-1)·kg(-1) iv）对 PDE5 的抑制都能在休息和运动时以及在预先收缩的分离冠状动脉小动脉中产生冠状动脉舒张。相比之下，TEZOSENTAN 在 EMD360527 存在的情况下，无论是在体内还是在体外，都未能进一步引起冠状动脉舒张。重要的是，EMD360527（3μM）和 cGMP 类似物 8-Br-cGMP（100μM）对分离的猪冠状动脉小动脉中 ET 诱导的收缩没有显著影响，这表明 ET 受体反应性不受影响。相反，PDE5 抑制和 cGMP 减弱了由 ET 前体 Big ET 引起的收缩，但仅在完整内皮的血管中，这表明 PDE5 抑制限制了小冠状动脉内皮中 ET 的产生。总之，PDE5 活性对冠状动脉阻力血管施加血管收缩作用，部分是通过增加内皮 ET 产生来介导的。
