NO stimulates soluble guanylate cyclase to produce the vasodilator cGMP. Phosphodiesterases (PDE) inactivate cGMP. We studied the hemodynamic effects of PDE inhibition with dipyridamole (DIP), a commercially available phosphodiesterase inhibitor, in a newborn lamb model of PPHN in which the fetal ductus arteriosus is ligated 10 days prior to delivery. At delivery (136 days), catheters were placed in the jugular vein, carotid artery, main pulmonary artery, and left atrium. An ultrasonic flow probe was placed around the main PA. We first measured the effect of 30 minute infusions of DIP alone. Mean aortic pressure (MAP) decreased by 22% and 25% following DIP at 0.1 (n=1) and 0.05 mg/kg/min (n=4) respectively. DIP at 0.01 mg/kg/min did not affect MAP (n=2). We then studied the systemic and pulmonary hemodynamic effects of DIP at 0.02 mg/kg/min for 30 min in 5 lambs with PPHN. In 4 of these lambs the effect of DIP followed by a 15 minute period of NO inhaled at 5 ppm was measured. Data for 15 min of inhaled NO alone (n=6) are provided for comparison. Hemodynamic data are presented in thetable. * p < 0.05 by ANOVA vs Before value.
DIP alone decreased MAP (18%), increased QP, and decreased PVR. In addition, PaO2 significantly increased (51±17 vs 119±38 mm Hg). The addition of inhaled NO to DIP caused a further increase in PaO2 (122± 58 vs 155 ± 58 mm Hg. p < 0.05) and tended to increase QP and decrease PAP and PVR further. We conclude that DIP alone, when infused at doses equivalent to those previously reported for the PDE inhibitor zaprinast(AJRCCM 1995; 152: 1605), produces marked systemic hypotension. At the lower dose of 0.02 mg/kg/min, DIP caused pulmonary and less marked systemic vasodilation. Inhaled NO with DIP further enhanced the effect of DIP. However, the marked synergy we previously reported between NO and ZAP was not seen, perhaps because systemic hypotension limited the dose of DIP. (Supported by AHA, NIH # HL 54705, and WCRF of Buffalo.)
