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 mechanisms, is an inhibitor of cGMP-specific phosphodiesterases (PDE5); it therefore has the potential to increase pulmonary vascular cGMP levels, lower pulmonary vascular resistance, augment iNO-induced pulmonary vasodilation, and attenuate excessive pulmonary vasoreactivity. To test dipyridamole in the pulmonary circulation, we studied pediatric patients undergoing cardiac catheterization who had severe resting pulmonary hypertension (Group 1; n = 11) or exaggerated acute hypoxia-induced pulmonary vasoconstriction (Group 2; n = 4). In Group 1, we compared the effects of iNO (20 ppm), dipyridamole (0.6 mg/kg), and combined treatments (iNO + dipyridamole) on pulmonary and systemic hemodynamics. In Group 2 we measured the pulmonary and systemic effects of dipyridamole while the patients were breathing room air and hypoxic gas mixtures (FIO2 = 0.16). One patient in Group 1 had a hypotensive response to dipyridamole and was exluded from study. In the remaining 12 studies done on 10 patients, iNO caused a selective decrease in mean pulmonary artery pressure (Ppa) and indexed pulmonary vascular resistance (PVRI) without affecting mean aortic pressure (Pao) or indexed systemic vascular resistance (SVRI). Dipyridamole decreased PVRI 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 change in Ppa, 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 the pulmonary-to-systemic resistance ratio (Rp/Rs) increased to suprasystemic levels during acute hypoxia. Pretreatment with dipyridamole blunted the increase in Ppa and Rp/Rs during repeat hypoxia, keeping Ppa at a subsystemic level and Rp/Rs < 1. We conclude that: (1) dipyridamole 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 hypoxic pulmonary vasoconstriction in children with exaggerated hypoxic pressor responses.
Ziegler
J W
JW
Department of Pediatrics, University of Colorado School of Medicine, and Children's Hospital, Denver, Colorado, USA. JIMWZ@AOL.COM
Ivy
D D
DD
Wiggins
J W
JW
Kinsella
J P
JP
Clarke
W R
WR
Abman
S H
SH
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006328:Cardiac Catheterization; D002302:Cardiac Output / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004176:Dipyridamole / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy; D007223:Infant; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology; D011652:Pulmonary Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D004176:Dipyridamole; D006152:Cyclic GMP