Hyporesponsiveness to inhaled nitric oxide in isolated, perfused lungs from endotoxin-challenged rats.
Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in patients with the adult respiratory distress syndrome (ARDS). Approximately 30% of ARDS patients fail to respond to iNO. Because sepsis syndrome often accompanies a decreased response to iNO, we investigated NO responsiveness in isolated, perfused lungs from rats exposed to lipopolysaccharide (LPS). Eighteen hours after intraperitoneal injection of 0.5 mg/kg LPS, rat lungs were isolated, perfused, and preconstricted with U-46619. Ventilation with 0.4, 4, and 40 parts per million by volume NO vasodilated LPS-pretreated lungs 75, 47, and 42% less than control lungs (P < 0.01 value differs at each concentration). The diminished vasodilatory response to iNO was associated with decreased NO-stimulated guanosine 3',5'-cyclic monophosphate (cGMP) release into the perfusate. Soluble guanylate cyclase activity did not differ in lung extracts from LPS-pretreated and control rats. LPS increased pulmonary cGMP-phosphodiesterase (PDE) activity by 40%. The PDE-sensitive cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate vasodilated lungs from LPS-pretreated rats less than lungs from control rats. In contrast, the PDE-insensitive 8-para-chlorophenylthioguanosine 3',5'-cyclic monophosphate vasodilated lungs equally from both groups. After LPS challenge, the rat pulmonary vasculature becomes hyporesponsive to iNO. Hyporesponsiveness to iNO appears partly attributable to increased pulmonary cGMP-PDE activity.
Holzmann
A
A
Department of Anesthesia, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Bloch
K D
KD
Sanchez
L S
LS
Filippov
G
G
Zapol
W M
WM
D000280:Administration, Inhalation; D000818:Animals; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D009569:Nitric Oxide / Q000008:administration & dosage*; D010477:Perfusion; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D008070:Lipopolysaccharides; D009569:Nitric Oxide