Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs.
BACKGROUND
Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb.


METHODS
Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis).


RESULTS
Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P <.05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P <.05). The alpha soluble guanylate cyclase (-45.7%) and beta soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P <.05), whereas phosphodiesterase 5 proteins levels were unchanged.


CONCLUSIONS
These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.
Thelitz
Stephan
S
Department of Cardiothoracic Surgery, University of California, San Francisco 94143-0106, USA.
Bekker
Janine M
JM
Ovadia
Boaz
B
Stuart
Regan B
RB
Johengen
Michael J
MJ
Black
Stephen M
SM
Fineman
Jeffrey R
JR
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D008168:Lung / Q000201:enzymology*; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D014665:Vasodilator Agents; D009569:Nitric Oxide; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D006152:Cyclic GMP