REGULATION OF THE ENDOGENOUS NO PATHWAY BY PROLONGED INHALED NO IN RATS

Nitric oxide (NO) modulates the endogenous NO-cGMP pathway. We determi ned whether prolonged inhaled NO downregulates the NO-cGMP pathway, wh ich may explain clinically observed rebound pulmonary hypertension. Ra ts were placed in a normoxic (N; 21% O-2) or hypoxic (H; 10% O-2) envi ronment with and without inhaled NO (20 parts/million) for 1 or 3 wk. Subsequently, nitric oxide synthase (NOS) and soluble guanylate cyclas e (GC) activity and endothelial NOS (eNOS) protein levels were measure d. Perfusate cGMP levels and endothelium-dependent and -independent va sodilation were determined in isolated lungs, eNOS protein levels and NOS activity were not altered by inhaled NO in N or H rats. GC activit y was decreased by 60 +/- 10 and 55 +/- 11% in N and H rats, respectiv ely, after 1 wk of inhaled NO but was not affected after 3 wk. Inhaled NO had no effect on perfusate cGMP in N lungs. Inhaled NO attenuated the increase in cGMP levels caused by 3 wk of H by 57 +/- 11%, but the re was no rebound in cGMP after 24 h of recovery. Endothelium-dependen t vasodilation was not altered, and endothelium-independent vasodilati on was not altered (N) or slightly increased (H, 10 +/- 3%) by prolong ed inhaled NO. In conclusion, inhaled NO did not alter the endogenous NO-cGMP pathway as determined by eNOS protein levels, NOS activity, or endothelium-dependent vasodilation under N and H conditions. GC activ ity was decreased after 1 wk; however, GC activity was not altered by 3 wk of inhaled NO and endothelium-independent vasodilation was not de creased.