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.
Sheridan
B C
BC
Department of Surgery, University of Colorado, Denver, Colorado, USA.
McIntyre
R C
RC
Meldrum
D R
DR
Fullerton
D A
DA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D004731:Endotoxins / Q000633:toxicity; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects*
D004731:Endotoxins; D010726:Phosphodiesterase Inhibitors; D009599:Nitroprusside; D000001:Calcimycin; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine