Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure

✍ Scribed by P Harrison; J Wendon; R Williams

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 150 KB
• Volume: 23
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510230520

✦ Synopsis

Patients with fulminant hepatic failure (FHF) have a of an apparently adequate cardiac output and arterial severe microcirculatory disturbance causing tissue hypoxygenation. Tissue hypoxia, which contributes to the oxia. Infusion of acetylcysteine improves survival and development of multiorgan failure and a poor prognoreduces the incidence of multiorgan failure by enhancsis, 3 develops because oxygen consumption becomes deing tissue oxygenation. Because the observed circulapendent on oxygen delivery over a greater range than tory effects of acetylcysteine in FHF are similar to and normal because of a reduced ability to extract oxygen. synergistic with those produced by the microcirculatory Even though oxygen delivery is most often increased, vasodilator prostacyclin, we postulated that acetylcysit may still be inadequate for tissue requirements. The teine might potentiate an endogenous vasodilator. Nitric pathogenesis of the impaired tissue oxygen extraction oxide, a vasodilator that activates soluble guanylate cyis poorly understood but is thought to be the conseclase, is a possible candidate as plasma cyclic 3,5-guanosine monophosphate (cGMP) is raised in FHF, and in quence of microvascular obstruction by activated cells, vitro acetylcysteine has been found to enhance soluble the release of vasoactive substances, and endothelial guanylate cyclase activity. To investigate this possible cell damage caused by release of oxygen free radicals. 5 mechanism further, plasma cGMP was measured before

In established FHF, infusion of the reduced thiol aceand after acetylcysteine infusion in 24 patients with FHF tylcysteine in a prospective, controlled trial reduced the and again in 6 patients after recovery from acute illness. incidence of organ failure and enhanced survival. Its cGMP levels were high in FHF during acute illness (memechanism of action is as yet unproved, but the obdian, 7.0 nmol/L [interquartile range, 2.6-10.0]) in comserved improvements in systemic 7 and cerebral 8 oxygen parison with levels taken after recovery (1.5 nmol/L [1.0-1.9]; P õ .05). Levels rose further after acetylcysteine extraction and consumption suggest that acetylcysinfusion in the FHF cases (mean increase, 204% [95% CI; teine acts by reducing tissue hypoxia. A study in anes-49 to /360]; P õ .01) but not in the cases after recovery thetized dogs with cardiac tamponade after endotoxin (38% [07 to /84]). There were no significant changes in challenge, showed that acetylcysteine has no effect on levels of plasma atrial natriuretic peptide (ANP) or cythe level of oxygen consumption at critical oxygen declic adenosine monophosphate (cAMP) (mean increases, livery, indicating that it does not directly stimulate 8% [06 to /22] and 17% [09 to /43], respectively). The oxygen consumption. 9 Critical oxygen delivery was sigfindings further support the hypothesis that the benefinificantly lower and the slope of the oxygen consumpcial hemodynamic effects of acetylcysteine in FHF are mediated by enhancing the activity of the nitric oxide/ tion-delivery-dependent line steeper in those dogs resoluble guanylate cyclase enzyme system. (HEPATOLOGY ceiving acetylcysteine, reflecting a greater extraction 1996;23:1067-1072.)

capability and consistent with a beneficial effect on the distribution of blood flow in the microcirculation. Be-Patients with fulminant hepatic failure (FHF), irrecause the observed effects of acetylcysteine on the cirspective of the cause, have a severe circulatory disturculation are similar to and synergistic with those probance characterized by hyperdynamic circulation 1 and duced by the microcirculatory vasodilator prostacyclin 7 the development of tissue hypoxia, even in the presence and because acetylcysteine is not a vasodilator in normal subjects, 7,10 we postulated that its mechanism of action must relate to potentiation of an endogenous vasodilator released in FHF. Nitric oxide, a short-lived Abbreviations: FHF, fulminant hepatic failure; cGMP, cyclic 3,5-guanosine monophosphate; ANP, atrial natriuretic peptide; cAMP, cyclic adenosine radical synthesized from L-arginine 11 that activates solmonophosphate. uble guanylate cyclase to form cyclic 3,5-guanosine From the Institute of Liver Studies, King's College School of Medicine and monophosphate (cGMP), 12 resulting in vasodilata-Dentistry, London, England. tion, 13 is a possible candidate because plasma cGMP is