Reversal of pulmonary capillary ischemia-reperfusion injury by rolipram, a cAMP phosphodiesterase inhibitor

• Published in: Journal of applied physiology (1985) Vol. 77; no. 2; p. 774
• Main Authors: Barnard, J W, Seibert, A F, Prasad, V R, Smart, D A, Strada, S J, Taylor, A E, Thompson, W J
• Format: Journal Article
• Language: English
• Published: United States 01.08.1994
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Adenine - metabolism; Adenylyl Cyclases - metabolism; Animals; Capillary Permeability - drug effects; Colforsin - pharmacology; Image Processing, Computer-Assisted; Isoproterenol - pharmacology; Lung - drug effects; Lung - pathology; Male; Pulmonary Circulation - drug effects; Pyrrolidinones - therapeutic use; Rats; Rats, Inbred Strains; Reperfusion Injury - drug therapy; Reperfusion Injury - pathology; Rolipram
• ISSN: 8750-7587
• DOI: 10.1152/jappl.1994.77.2.774

Isoproterenol (ISO) and forskolin, agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) via adenylyl cyclase activation, reverse lung injury associated with increased microvascular permeability. We studied the role of rolipram, a relatively isozyme-selective cAMP phosphodiesterase (PDE) inhibitor, in reversing increased capillary permeability due to ischemia-reperfusion (I/R), a form of oxidant injury in the lung, by using the isolated perfused rat lung model. Rolipram (2 microM) administered after 45 min of ischemia and 45 min of reperfusion reduced I/R-increased permeability as measured by the capillary filtration coefficient to control lung values. Computer image analysis of air space edema and perivascular cuffing, as well as wet-to-dry weight ratios, confirms the permeability reversal by rolipram administration. Rolipram inhibition of cAMP PDE in the lung was assessed by using [3H]adenine prelabeling adapted for the whole lung and perfusate [3H]cAMP accumulation. Rolipram failed to increase perfusate cAMP alone but dramatically increased perfusate cAMP above ISO alone. Dose-response relationships of ISO or rolipram show a close correlation of the half-maximal effective dose (ED50) for injury reversal and perfusate cAMP production. The combination of rolipram and ISO produced synergistic reversal of I/R injury. We conclude that reversal of I/R-induced increased microvascular permeability can be achieved with rolipram and that the mechanism of action of rolipram is probably through PDE isozyme-selective inhibition. The similarity of the ED50 values for cAMP efflux and reversal of permeability increases also supports a close coupling between cAMP accumulation and endothelial cell permeability.