IN-VIVO EVIDENCE OF ENHANCED GUANYLYL CYCLASE ACTIVATION DURING THE HYPERDYNAMIC CIRCULATION OF ACUTE LIVER-FAILURE

Nitric oxide and atrial natriuretic peptides are the main activators o f guanylyl cyclases, which transform GTP into cyclic GMP and thereby c ontribute to the decrease of vascular tone. To investigate the increas e, if any, of plasma cyclic GMP concentrations in human patients with hyperdynamic circulation resulting from acute liver failure and to asc ertain whether guanylyl cyclase activation is involved in the decline of systemic vascular resistance that occurs in this pathophysiological condition, we simultaneously recorded hemodynamic data and cyclic GMP levels in patients with fulminant liver failure before and after live r transplantation and in normokinetic patients undergoing abdominal no nseptic surgery. We also compared these data with those recorded in pa tients with hyperkinetic shock resulting from gram-negative sepsis or nitric oxide-independent vasomotor agent (carbamate) overdose. In all these patients we simultaneously studied kidney function, platelet cou nts and atrial natriuretic peptides. Patients with fulminant liver fai lure had higher cyclic GMP concentrations than did control patients un dergoing abdominal surgery (11.02 +/- 1.55 pmol . ml-1 vs. 1.77 +/- 0. 18 pmol . ml-1 p < 0.00 1). At similar heart-loading conditions these concentrations were lower than those in gram-negative septic shock (18 .2 +/- 1.35 pmol . ml-1, p < 0.05) but higher than those in carbamate- induced shock (3.6 +/- 0.7 pmol . ml-1, p < 0.01). In addition, cyclic GMP concentrations significantly decreased from the fulminant liver f ailure period to the posttransplantation period, although atrial natri uretic peptide levels did not change significantly and kidney function worsened. During the period of fulminant liver failure, cyclic GMP le vels correlated with the decline in peripheral resistance but not with other hemodynamic or biological data. With the improvement of periphe ral resistance after the transplantation procedure, they did not furth er correlate with systemic vascular resistance, only with creatininemi a. Together these results suggest that guanylyl cyclase activation is involved in the low vascular resistance observed during acute hepatoce llular syndrome; furthermore, they indicate that particulate guanylyl cyclase activation only partially explains the increase in cyclic GMP observed during fulminant liver failure and put forward a role for sol uble guanylyl cyclase activators such as nitric oxide.