title: The PDE inhibitor zaprinast enhances NO-mediated protection against vascular leakage in reperfused lungs.
abstract: Disruption of endothelial barrier properties with development of noncardiogenic pulmonary edema is a major threat in lung ischemia-reperfusion (I/R) injury that occurs under conditions of lung transplantation. Inhaled nitric oxide (NO) reduced vascular leakage in lung I/R models, but the efficacy of this agent may be limited. We coadministered NO and zaprinast, a cGMP-specific phosphodiesterase inhibitor, to further augment the NO-cGMP axis. Isolated, buffer-perfused rabbit lungs were exposed to 4.5 h of warm ischemia. Reperfusion provoked a transient elevation in pulmonary arterial pressure and a negligible rise in microvascular pressure followed by a massive increase in the capillary filtration coefficient and severe lung edema formation. Inhalation of 10 parts/million of NO or intravascular application of 100 microM zaprinast on reperfusion both reduced pressor response and moderately attenuated vascular leakage. Combined administration of both agents induced no additional vasodilation at constant microvascular pressures, but additively protected against capillary leakage paralleled by a severalfold increase in perfusate cGMP levels. In conclusion, combining low-dose NO inhalation and phosphodiesterase inhibition may be suitable for the maintenance of graft function in lung transplantation by amplifying the beneficial effect of the NO-cGMP axis and avoiding toxic effects of high NO doses.
authors.affiliation: Department of Internal Medicine, Justus-Liebig University, 35385 Giessen, Germany. hartwig.schuette@innere.med.uni-giessen.de
authors.forename: H
authors.initials: H
authors.lastname: Schütte
authors.forename: M
authors.initials: M
authors.lastname: Witzenrath
authors.forename: K
authors.initials: K
authors.lastname: Mayer
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: A
authors.initials: A
authors.lastname: Schell
authors.forename: S
authors.initials: S
authors.lastname: Rosseau
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D003187:Compliance; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D009929:Organ Size / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011688:Purinones / Q000494:pharmacology*; D011817:Rabbits; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009569:Nitric Oxide; C011145:zaprinast; D006152:Cyclic GMP