Rolipram and Isoproterenol Reverse Platelet Activating Factor-Induced Increases in Pulmonary Microvascular Permeability and Vascular Resistance

Abstract

Platelet activating factor (PAF) is an important mediator of pulmonary microvascular endothelial cell (PMVEC) injury in sepsis. Membrane receptors for PAF have been identified on PMVECs and mediate its actions at least in part by protein kinase C activation. Since rolipram, a family IV cyclic AMP phosphodiesterase inhibitor, and isoproterenol, an adenylate cyclase activator, both reverse ischemia-reperfusion-induced lung permeability, we studied the effects of these agents on PAF-induced pulmonary microvascular permeability. The isolated rat lung model was used in which lungs were ventilated and buffer perfused at constant flow while suspended from a force transducer to monitor lung weight along with arterial ( P a) and venous ( P v) pressures. Control lungs ( n = 6) were infused with PAF (40 nmole/kg) via an arterial port and the capillary permeability coefficient ( K f,c) was determined at 0, 15, and 60 min. The remaining lungs were randomized for infusion with either rolipram ( n = 4, 20 μmole/kg) or isoproterenol ( n = 4, 5 μmole/kg) via an arterial port 30 min after injury with PAF. In the rolipram- and isoproterenol-treated groups, the K f,c was determined 15 and 60 min postinfusion with these agents. The control group showed significant elevation in the K f,c and total pulmonary resistance ( R t). At 15 and 60 min, rolipram and isoproterenol reversed PAF injury as shown by the significant improvement in the K f,c and R t. These findings support the concept that increased cyclic AMP is an important mediator in the reversal of PAF-increased PMVEC permeability and pulmonary resistance.