CYCLIC-NUCLEOTIDES AND VASOACTIVE-INTESTINAL-PEPTIDE PRODUCTION IN A RABBIT MODEL OF ESCHERICHIA-COLI SEPTICEMIA

Nitric oxide and vasoactive intestinal peptide (VIP) are potent vasodi lators and postulated as inducers of hypotension. These mediators acti vate guanylate cyclase and adenylate cyclase, respectively, with subse quent biosynthesis of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) producing vascular smooth muscle relax ation and vasodilatation. Cyclic nucleotides and VIP were evaluated du ring Escherichia coli septicemia in two groups of rabbits; 1) sepsis a lone and 2) sepsis and a competitive inhibitor of nitric oxide synthas e, NG-monomethyl-L-arginine, Arterial blood was obtained for determina tion of bacteremia, lactic acidemia, nucleotides, nitrites, and VIP le vels. Significant bacteremia, endotoxemia, tachycardia, lactic acidosi s, and hypotension occurred in all animals (P < 0.005), Circulating bl ood levels of cGMP, nitrites, cAMP, and VIP (P < 0.005) increased with development of shock, The NG-monomethyl-L-arginine treated animals ha d less cGMP, nitrites, cAMP, and VIP produced (P < 0.01). Plasma cGMP levels remained stable, suggesting that stimulated phagocytes in whole blood were responsible for increased cGMP levels. Infusion of VIP pro duced profound hypotension and tactic acidemia. Results of these exper iments provide definitive evidence that nitric oxide and VIP are media tors during septic shock and their messengers are cGMP and cAMP, respe ctively, In addition, phagocytic stimulation with increased production of cGMP may initiate shock, with these mediators acting synergistical ly to prolong hypotension.