Proinflammatory stimuli produce expression of inducible NO-synthase (iNOS)
within blood vessels and are associated with impaired endothelium-dependent
relaxation. Gene transfer of iNOS was used to test the hypothesis that exp
ression of iNOS in blood vessels produces impairment of NO-dependent relaxa
tion as well as contraction. An adenoviral vector containing cDNA for murin
e iNOS, AdCMViNOS, and a control virus, AdCMVBgIII, were used for gene tran
sfer to rabbit carotid arteries in vitro and in vivo. After gene transfer o
f iNOS in vitro, contractile responses to KCl, phenylephrine, and U46619 we
re impaired. Relaxation in response to acetylcholine, ADP, A23187, and nitr
oprusside was also impaired. For example, maximum relaxation of vessels to
acetylcholine (10 mu mol/L) was 78 +/-4% (mean +/- SE) after AdBgIII (10(10
.5) plaque-forming units) and 34 +/-5% after AdiNOS (10(10.5) plaque-formin
g units, P <0.05). NO-independent relaxation in response to 8-bromo-cGMP an
d papaverine was not impaired after AdiNOS. Contraction and relaxation were
improved in carotid arteries expressing iNOS by aminoguanidine and L-N-imi
noethyl lysine, inhibitors of iNOS. After intraluminal gene transfer of iNO
S in vivo, contraction of vessels in vitro was normal, but responses to ace
tylcholine were impaired. In summary, the major finding is that NO-dependen
t relaxation is impaired in arteries after gene transfer of iNOS in vitro a
nd in vivo. Thus, expression of iNOS per se impairs NO-dependent relaxation
.