Phosphodiesterase inhibition overcomes pulmonary vasomotor dysfunction in acute lung injury.

Production of cGMP is impaired in endotoxin-induced acute lung injury. This results in dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation and, therefore, pulmonary hypertension. We hypothesized that cyclic nucleotide phosphodiesterase (PDE) inhibition would attenuate endotoxin-induced impairment to cGMP-mediated mechanisms of pulmonary vasorelaxation. The purpose was to examine the effect of stimulating cGMP production with concurrent inhibition of cGMP catabolism by PDE inhibition following endotoxin-induced acute lung injury. Isolated pulmonary arterial rings from rats (n = 5) were studied 6 hrs after endotoxin (20 mg/kg ip) or saline. In a third group (n = 5), PDE inhibition was accomplished with in vitro 3-isobutyl-1-methylxanthine (IBMX, 1 microM for 30 min). Cyclic GMP-mediated relaxation was interrogated by stimulating (1) endothelium-dependent mechanisms with the receptor-dependent agonist acetylcholine and the receptor-independent agonist A23187, a calcium ionophore, and an (2) endothelium-independent mechanism with sodium nitroprusside. PDE inhibition attenuated endotoxin-induced vasomotor dysfunction. A two-pronged approach-stimulating cGMP production and preventing cGMP catabolism with PDE inhibition-may offer a therapeutically accessible mechanism to overcome vasomotor dysfunction in acute lung injury.