Effect of time and vascular pressure on permeability and cyclic nucleotides in ischemic lungs.
We previously found that increased intravascular pressure decreased ischemic lung injury by a nitric oxide (NO)-dependent mechanism (Becker PM, Buchanan W, and Sylvester JT. J Appl Physiol 84: 803-808, 1998). To determine the role of cyclic nucleotides in this response, we measured the reflection coefficient for albumin (sigma(alb)), fluid flux (), cGMP, and cAMP in ferret lungs subjected to either 45 min ("short"; n = 7) or 180 min ("long") of ventilated ischemia. Long ischemic lungs had "low" (1-2 mmHg, n = 8) or "high" (7-8 mmHg, n = 6) vascular pressure. Other long low lungs were treated with the NO donor (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium -1, 2-diolate (PAPA-NONOate; 5 x 10(-4) M, n = 6) or 8-bromo-cGMP (5 x 10(-4) M, n = 6). Compared with short ischemia, long low ischemia decreased sigma(alb) (0.23 +/- 0.04 vs. 0.73 +/- 0.08; P < 0.05) and increased (1.93 +/- 0.26 vs. 0.58 +/- 0.22 ml. min(-1). 100 g(-1); P < 0.05). High pressure prevented these changes. Lung cGMP decreased by 66% in long compared with short ischemia. Lung cAMP did not change. PAPA-NONOate and 8-bromo-cGMP increased lung cGMP, but only 8-bromo-cGMP decreased permeability. These results suggest that ischemic vascular injury was, in part, mediated by a decrease in cGMP. Increased vascular pressure prevented injury by a cGMP-independent mechanism that could not be mimicked by administration of exogenous NO.
Pearse
D B
DB
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions at the Asthma and Allergy Center, Hopkins Bayview Medical Center, Baltimore, Maryland 21224, USA. dpearse@welch.jhu.edu
Becker
P M
PM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D012121:Respiration, Artificial; D012709:Serum Albumin / Q000378:metabolism; D014867:Water / Q000378:metabolism
D006834:Hydrazines; D020030:Nitric Oxide Donors; D009712:Nucleotides, Cyclic; C112653:PAPA NONOate; D012709:Serum Albumin; D014867:Water; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D000242:Cyclic AMP; D006152:Cyclic GMP