In vivo evidence of enhanced guanylyl cyclase activation during the hyperdynamic circulation of acute liver failure

Abstract

Nitric oxide and atrial natriuretic peptides are the main activators of guanylyl cyclases, which transform GTP into cyclic GMP and thereby contribute to the decrease of vascular tone. To investigate the increase, if any, of plasma cyclic GMP concentrations in human patients with hyperdynamic circulation resulting from acute liver failure and to ascertain 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 liver transplantation and in normokinetic patients undergoing abdominal nonseptic surgery. We also compared these data with those recorded in patients with hyperkinetic shock resulting from gram-negative sepsis or nitric oxide-independent vasomotor agent (carbamate) over-dose. In all these patients we simultaneously studied kidney function, platelet counts and atrial natriuretic peptides. Patients with fulminant liver failure had higher cyclic GMP concentrations than did control patients undergoing abdominal surgery (11.02 +/- 1.55 pmol.ml-1 vs. 1.77 +/- 0.18 pmol.ml-1, p < 0.001). 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 failure period to the posttransplantation period, although atrial natriuretic peptide levels did not change significantly and kidney function worsened.(ABSTRACT TRUNCATED AT 250 WORDS)

The response to methylene blue in patients with severe hypotension during liver transplantation

“…Liver cirrhosis and liver failure are accompanied by increased activity of the guanylate cyclase system [13,14]. Endogenous NO and cannabinoids both act through the guanylate cyclase system [15,16], and cause decreased systemic vascular tone and the cardiac contractility seen in advanced liver failure [5,13,17].…”

Increased protein kinase A regulatory subunit content and cGMP binding in erythrocyte membranes in liver cirrhosis

“…Plasma cGMP is increased in patients with liver cirrhosis [1] or acute liver failure [2]. Urinary cGMP excretion is enhanced in liver cirrhosis [16].…”

“…Plasma cGMP concentration is increased in patients with liver disease [1,2]. In contrast, cGMP concentration is reduced in lymphocytes of patients with liver cirrhosis or hepatitis [3], who show a significantly altered cGMP homeostasis.…”

Acute liver failure: current management and future prospects

“…Also of importance is the observation from studies in animals that the renal dysfunction was manifest even when the renal blood flow was normal suggesting that other factors may be important in initiating the renal dysfunction in acute liver failure [33,36]. The pathophysiologic mechanisms underlying these hemodynamic disturbances are unclear but increased nitric oxide production and cGMP has been demonstrated during the later stages of the disease [37]. Unlike cirrhosis, nitric oxide does not seem to be involved as a factor initiating the vascular disturbances.…”