van Duin Richard W B, Stam Kelly, Uitterdijk André, Bartelds Beatrijs, Danser A H Jan, Reiss Irwin K M, Duncker Dirk J, Merkus Daphne
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands.
Department of Pediatrics/Neonatology, Erasmus MC-Sophia Children's Hospital, 3015 GD Rotterdam, The Netherlands.
J Clin Med. 2019 Aug 12;8(8):1204. doi: 10.3390/jcm8081204.
Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP/HF vs. HP/LF territories. Swine underwent pulmonary vein banding (PVB; = 7) or sham surgery ( = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP/LF and HP/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP/LF and HP/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP/HF and sensitivity to bradykinin was lower in PVB HP/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP/HF vs. HP/LF vasculature.
由肺静脉狭窄（PVS）导致的肺动脉高压（PH）极难治疗。理想的治疗不应针对引流至狭窄静脉的高压/低流量（HP/LF）血管系统，而仅针对引流至未受影响肺静脉的高压/高流量（HP/HF）血管系统，降低血管阻力和压力而无肺水肿风险。我们旨在评估PH发展过程中PVS时一氧化氮（NO）途径的活性，并研究对NO途径的干预是否对HP/HF与HP/LF区域的血管舒张有不同影响。猪接受肺静脉环扎术（PVB；n = 7）或假手术（n = 6），并长期植入仪器以评估PH的进展。每两周评估一次肺对外源性NO（硝普钠，SNP）的敏感性以及内源性NO的作用。在PVB或假手术后12周评估肺血管对磷酸二酯酶-5（PDE5）抑制的舒张反应。在术后12周处死后，进一步研究对从HP/LF和HP/HF区域分离的肺小动脉中NO途径的干预。与假手术组相比，PVB后长达8周，体内肺血管对SNP的舒张反应以及对内皮型一氧化氮合酶（eNOS）抑制的肺血管收缩反应均无差异。然而，在PVB后10周和12周，PVB组中对SNP的体内肺血管舒张更大。同样，PVB组中对eNOS抑制的血管收缩更大，尤其是在运动期间，而PVB组中对PDE5抑制的肺血管舒张在休息和运动时均更大。在分离的肺小动脉中，无论HP/LF和HP/HF如何，PVB组与假手术组对NO供体SNP的敏感性相似，而PVB组中HP/HF对PDE5抑制剂西地那非的敏感性较低，PVB组中HP/LF对缓激肽的敏感性较低。总之，PVB组中NO的可用性和敏感性均增加。一氧化氮敏感性增加并非PDE5活性降低的结果，因为PDE5活性甚至增加。一些血管舒张剂对HP/HF与HP/LF血管系统有不同影响。
