VASCULAR EFFECTS OF LPS IN MICE DEFICIENT IN EXPRESSION OF THE GENE FOR INDUCIBLE NITRIC-OXIDE SYNTHASE

The inducible isoform of nitric oxide synthase (iNOS) is expressed aft er systemic administration of lipopolysaccharide (LPS). The importance of expression of iNOS in blood vessels is poorly defined. Because nit ric oxide from iNOS may alter vasomotor function, we examined effects of LPS on vasomotor function in carotid arteries from iNOS-deficient m ice. We studied contraction of the carotid artery from wild-type and i NOS-deficient mice in vitro 12 h after injection of LPS (20 mg/kg ip). Contractile responses to PGF(2 alpha) (3-30 mu M) and thromboxane A(2 ) analog (U-46619; 3-100 nM) were evaluated using vascular rings from mice treated with vehicle or LPS. Maximum force of contraction generat ed by rings in response to PGF(2 alpha) was 0.39 +/- 0.02 and 0.25 +/- 0.01 (SE) g (n = 14) in vehicle and LPS-treated wild-type mice, respe ctively (P < 0.001 vs. vehicle). Thus LPS reduced constrictor response s in wild-type mice. Thiocitrulline and aminoguanidine (inhibitors of iNOS) improved contractile responses from LPS-treated wild-type vessel s. Indomethacin also improved constrictor responses in arteries from w ild-type mice injected with LPS. In contrast, contraction of the carot id arteries in response to PGF(2 alpha) and U-46619 was not impaired i n LPS-treated iNOS-deficient mice, and contraction was not altered by inhibitors of iNOS. Expression of iNOS mRNA was confirmed using RT-PCR in carotid arteries hom wild-type mice after injection of LPS but not vehicle. PCR products for iNOS were not observed in iNOS-deficient mi ce. These findings provide the first direct evidence that iNOS mediate s impairment of vascular contraction after treatment with LPS.