DIETHYLDITHIOCARBAMATE AMELIORATES THE EFFECT OF LIPOPOLYSACCHARIDE ON BOTH INCREASED NITRITE PRODUCTION BY VASCULAR SMOOTH-MUSCLE CELLS AND DECREASED CONTRACTILE RESPONSE OF AORTIC RINGS

The depression of vasoconstrictor responsiveness caused by bacterial l ipopolysaccharide (LPS) is mediated, in part, by the induction of nitr ic oxide synthase (NOS) and the resultant increase in nitric oxide pro duction by vascular smooth muscle. The present study evaluated the abi lity of the antioxidant, diethyldithiocarbamate (DDTC), to attenuate t he LPS-stimulated induction of NOS in cultured vascular smooth muscle cells (VSMC) and the depression of in vitro vascular reactivity caused by LPS administration to rats. The LPS-stimulated increase in nitrite production by cultured VSMC was inhibited 85% by DDTC (100 mu M). Whe n VSMC were stimulated with a combination of LPS, interferon-gamma (IN F) and tumor necrosis factor (TNF) nitrite production was fi-fold grea ter than with LPS alone. DDTC inhibited 49% of the increase caused by LPS plus INF and TNF. Aortic rings taken from animals injected with LP S showed a depression of maximum force in response to phenylephrine wh ich was reversed by inhibition of NOS activity. Pretreatment of animal s with DDTC attenuated this depression of vascular reactivity. The DDT C treatment did not reduce the increase in serum TNF levels caused by LPS. These results suggest that DDTC can attenuate the LPS-stimulated induction of NOS in vascular smooth muscle and may thereby ameliorate the impairment of vascular reactivity.