Cytokine regulation of inducible nitric oxide synthase in vascular smooth muscle cells

NO is an important mediator in sepsis. It has been unequivocally established that it is the major determinant in the vasodilatation and consequent hypotension in experimental animals following the administration of LPS. It is cytotoxic, particularly in combination with superoxide anions, and exerts negative inotropic and chronotropic effects on the heart. The exact role that these functions play in sepsis, however, remain unclear. Similarly, its immunomodulatory and cerebral effects, although potentially important, remain of uncertain significance in sepsis. Regulation of such a pivotal molecule is clearly extremely important: the data described here show that not only is this regulation extremely complex, but it appears to vary in different cell types. The implication of this finding for future clinical work is clear. NO production is not all bad: in some circumstances, it may be desirable to differentially regulate iNOS activity such that production is restricted in some cell types but not in others. The work described here begins to offer the possibility of identifying new molecular targets which allow this kind of differential regulation.