Thusu K G, Morin F C, Russell J A, Steinhorn R H
Department of Pediatrics, State University of New York at Buffalo, USA.
Am J Respir Crit Care Med. 1995 Nov;152(5 Pt 1):1605-10. doi: 10.1164/ajrccm.152.5.7582302.
We investigated the effect of zaprinast (M&B 22948), a specific cGMP phosphodiesterase inhibitor, on pulmonary arteries isolated from lambs with persistent pulmonary hypertension following prenatal ligation of the ductus arteriosus. Relaxations to sodium nitroprusside, which donates nitric oxide inside the smooth muscle cell, were significantly decreased in pulmonary arteries from ligated lambs. Pretreatment with 3 x 10(-5) M zaprinast restored them to levels close to those observed in untreated arteries from control animals. Further studies in intact newborn lambs were then conducted under three experimental conditions: (1) NO inhalation at 6 ppm, (2) zaprinast infusion at 0.05 mg/kg/min, and (3) combination therapy of zaprinast infusion in addition to inhaled NO at 6 ppm. Combined therapy with NO and zaprinast decreased the pulmonary artery pressure (34.3 +/- 3%) and pulmonary vascular resistance (64 +/- 7%) and increased pulmonary blood flow (88 +/- 34%) and postductal PaO2 (287 +/- 34%) to a significantly greater extent than NO alone, zaprinast alone, or the sum of these two responses, indicating a true synergistic effect. Zaprinast pretreatment also markedly increased the duration of pulmonary vasodilation to nitric oxide. There was no effect on systemic blood pressure with the combined therapy. We conclude that zaprinast pretreatment significantly enhances the effect of sodium nitroprusside on isolated pulmonary arteries, as well the effect of inhaled NO at 6 ppm in newborn lambs with persistent pulmonary hypertension. We speculate that phosphodiesterase inhibition may increase the response rate to NO or allow the use of much lower inhaled concentrations of NO.
我们研究了特异性环磷酸鸟苷（cGMP）磷酸二酯酶抑制剂扎普司特（M&B 22948）对产前结扎动脉导管后发生持续性肺动脉高压的羔羊离体肺动脉的作用。在结扎羔羊的肺动脉中，对能在平滑肌细胞内释放一氧化氮的硝普钠的舒张反应显著降低。用3×10⁻⁵M扎普司特预处理可将其恢复至接近未处理的对照动物动脉中观察到的水平。随后在完整的新生羔羊中进行了三种实验条件下的进一步研究：（1）吸入6 ppm一氧化氮；（2）以0.05 mg/kg/min的速度输注扎普司特；（3）除吸入6 ppm一氧化氮外还输注扎普司特的联合治疗。一氧化氮和扎普司特联合治疗降低肺动脉压（34.3±3%）和肺血管阻力（64±7%），增加肺血流量（88±34%）和导管后动脉血氧分压（287±34%）的程度明显大于单独使用一氧化氮、单独使用扎普司特或这两种反应之和，表明存在真正的协同作用。扎普司特预处理还显著延长了肺动脉对一氧化氮舒张的持续时间。联合治疗对体循环血压无影响。我们得出结论，扎普司特预处理显著增强了硝普钠对离体肺动脉的作用，以及对患有持续性肺动脉高压的新生羔羊吸入6 ppm一氧化氮的作用。我们推测磷酸二酯酶抑制可能会提高对一氧化氮的反应率，或允许使用低得多的一氧化氮吸入浓度。
