EFFECTS OF DIPYRIDAMOLE AND INHALED NITRIC-OXIDE IN PEDIATRIC-PATIENTS WITH PULMONARY-HYPERTENSION

Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation by increasing pulmonary vascular levels of cyclic guanosine monophosphate (cGMP). Dipyridamole, a drug with several putative vasodilator mechan isms, is an inhibitor of cGMP-specific phosphodiesterases (PDE5); it t herefore has the potential to increase pulmonary vascular cGMP levels, lower pulmonary vascular resistance, augment iNO-induced pulmonary va sodilation, and attenuate excessive pulmonary vasoreactivity. To test dipyridamole in the pulmonary circulation, we studied pediatric patien ts undergoing cardiac catheterization who had severe resting pulmonary hypertension (Group 1; n = 11) or exaggerated acute hypoxia-induced p ulmonary vasoconstriction (Group 2; n = 4). In Group 1, we compared th e effects of iNO (20 ppm), dipyridamole (0.6 mg/kg), and combined trea tments (iNO + dipyridamole) on pulmonary and systemic hemodynamics. In Group 2 we measured the pulmonary and systemic effects of dipyridamol e while the patients were breathing room air and hypoxic gas mixtures (F1(O2) = 0.16). One patient In Group 1 had a hypotensive response to dipyridamole and was exluded from study. In the remaining 12 studies d one on 10 patients, iNO caused a selective decrease in mean pulmonary artery pressure ((Ppa) over bar) and indexed pulmonary vascular resist ance (PVRI) without affecting mean aortic pressure ((Pao) over bar) or indexed systemic vascular resistance (SVRI). Dipyridamole decreased P VRI to similar values as did iNO, but this effect was primarily due to an increase in cardiac index (CI), and was not associated with any ch ange in (Ppa) over bar, and was associated with a decrease in Pao and SVRI. In comparison with individual treatments, combined therapy (iNO + dipyridamole) did not augment pulmonary vasodilation in the group as a whole; however, in 50% of patients, combined therapy decreased PVRI by 20% more than did iNO or dipyridamole alone. In Group 2, Ppa and t he pulmonary-to-systemic resistance ratio (Rp/Rs) increased to suprasy stemic revels during acute hypoxia. Pretreatment with dipyridamole blu nted the increase in Ppa and Rp/Rs during repeat hypoxia, keeping Ppa at a subsystemic level and Rp/Rs < 1. We conclude that: (1) dipyridamo le nonselectively reduces PVRI, primarily through an increase in CI; ( 2) in combination with iNO, dipyridamole augments the decrease in PVRI in some patients; and (3) dipyridamole blunts the severity of acute h ypoxic pulmonary vasoconstriction in children with exaggerated hypoxic presser responses.