title: Inhaled nitric oxide and nifedipine have similar effects on lung cGMP levels in rats.
abstract: Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible down-regulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg x kg(-1) x day(-1). The lungs were then isolated and perfused with physiologic saline. Perfusate cGMP, prostacyclin, and cAMP levels were measured. Perfusate cGMP was not altered by inhaled NO or nifedipine in normoxic or MCT rats. Although hypoxia significantly increased cGMP by 128%, both inhaled NO and nifedipine equally prevented the hypoxic increase. Inhibition of the NO/cGMP pathway with N(G)-nitro-L-arginine methyl ester (L-NAME) decreased cGMP by 72% and 88% in normoxic and hypoxic lungs. Prostacyclin and cAMP levels were not altered by inhaled NO or nifedipine. L-NAME significantly decreased cGMP levels, whereas inhaled NO had no effect on cGMP in normoxic or MCT lungs, suggesting that inhaled NO does not inhibit the NO/cGMP pathway. Inhaled NO decreased cGMP in hypoxic lungs, however, nifedipine had the same effect, which indicates the decrease is not specific to inhaled NO.
  
  
  CONCLUSIONS
  High pulmonary pressure after discontinuation of inhaled nitric oxide (NO) may be secondary to a decrease in the natural endogenous NO vasodilator. This rat study suggests that inhaled NO either does not alter endogenous NO or that it has similar effects as nifedipine.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, Charlottesville 22906-0010, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Horstman
authors.forename: D A
authors.initials: DA
authors.lastname: McCall
authors.forename: D U
authors.initials: DU
authors.lastname: Frank
authors.forename: G F
authors.initials: GF
authors.lastname: Rich
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D006152:Cyclic GMP / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000032:analysis; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D016686:Monocrotaline / Q000009:adverse effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000008:administration & dosage / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D011042:Poisons / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D011042:Poisons; D014665:Vasodilator Agents; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D016686:Monocrotaline; D011464:Epoprostenol; D000242:Cyclic AMP; D006152:Cyclic GMP; D009543:Nifedipine; D019331:NG-Nitroarginine Methyl Ester