Site-specific effect of guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition in isolated lamb lungs.
OBJECTIVE
To determine the effect of combining inhaled nitric oxide (NO) with an inhibitor of guanosine 3',5'-cyclic monophosphate-specific phosphodiesterase on total and segmental lung resistances.


METHODS
A controlled laboratory study in isolated blood-perfused lungs prepared from lambs.


METHODS
Animal research facility affiliated with a university teaching hospital.


METHODS
Five newborn lambs at <48 hrs of life.


METHODS
Isolated blood-perfused lungs were prepared and treated with indomethacin (40 microg/mL) to inhibit prostaglandin synthesis. After a baseline period of normoxia (28% oxygen), pulmonary hypertension was induced with the thromboxane mimetic U46619 (0.1-0.4 microg/kg/min). During pulmonary hypertension, lungs were studied with inhaled NO only, with infusion of zaprinast only (0.25 mg/kg bolus and 0.05 mg/kg/min infusion), and with a combination of the two. For each study condition, the total pressure decrease across the lung was measured, and the inflow-outflow occlusion technique was used to partition the total pressure gradient measured at constant flow (100 mL/kg/min) into gradients across relatively noncompliant large arteries and veins and more compliant small arteries and veins.


RESULTS
U46619 infusion produced significant pulmonary vasoconstriction. The combination of inhaled NO and zaprinast decreased the total pressure decrease across the lung significantly more than NO alone. This effect was primarily attributable to a significantly greater decrease in gradient across the small artery segment after inhaled NO and zaprinast compared with NO alone.


CONCLUSIONS
Guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition with zaprinast enhances the effect of inhaled NO, particularly in conditions in which small arteries represent the site of resistance. Phosphodiesterase inhibition may be a promising adjunct to inhaled NO for the treatment of persistent pulmonary hypertension.
Steinhorn
R H
RH
Department of Pediatrics, State University of New York at Buffalo, NY, USA.
Gordon
J B
JB
Tod
M L
ML
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D006152:Cyclic GMP / Q000037:antagonists & inhibitors*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011688:Purinones / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D016861:Cyclooxygenase Inhibitors; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C011145:zaprinast; D006152:Cyclic GMP; D007213:Indomethacin