ABSTRACT
Septic shock is characterized by a progressive loss o f m icrovascular, and specifically re s is tan ce a r te r io la r to n e a n d co n tro l . N um erous m ediation systems have been im plicated in the pathogenesis o f such dysfunc tion. Recent evidence points to a central role o f lipopolysaccharide (LPS)-induced leuko cyte cytokine elaboration, w ith subsequent upregulation o f the inducible form o f n itric ox ide syn thase (iN O S) w ith in vascu la r sm ooth m uscle cells (VSMC) o f the arte ri olar w all.1 Over the last 10 years, we and o ther groups have dem onstrated a m arked release o f vasoactive neuropeptides du ring the acute phases o f endotoxem ia and sep sis. O f these, calcitonin gene-related peptide (CGRP) seems to be the best docum ented2'4 and potentially the m ost po ten t inh ib ito r o f a rte rio la r con trac tile fu n c tio n .5 T here is little doub t th a t CGRP, together w ith N O g e n e ra te d fro m iN O S u p re g u la tio n , is cap ab le o f p ro fo u n d d ire c t a c tio n s on VSMC and arterio lar contractile function during sepsis. Recently, however, we becam e in terested in the possibility tha t, in add i tion to its acute, direct actions on VSMC contractile function , CGRP m aybe respon sible fo r m o d u la tin g th e cy tok ine-iN O S -N O axis itself. The cen tral hypothesis o f this investigation was therefore th a t CGRP is capable o f m odu la ting LPS-and cyto kine-stim ula ted N O form ation . Further, it
was hypo thesized th a t such m o d u la tio n occurs via cA M P/protein kinase A (PKA)- dependent influences on VSMC iNOS gene transcrip tion .
