Ollosson, R.; (2008) S-nitrosothiols, nitric oxide and platelet and vascular dysfunction in cirrhosis. Doctoral thesis , University of London.

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Abstract

Elevated plasma concentration of the known platelet inhibiting species S-nitrosothiols are correlated for the first time to platelet dysfunction in the bile duct ligated (BDL) cirrhotic rat. Further, a BDL model of cirrhosis has been established and characterised in a strain of analbuminaemic rats and a correlation made between a protection against S-nitrosothiol formation conferred by analbuminaemia and less dysfunction in platelet aggregation following induction of endotoxaemia and cirrhosis. Also, it has been demonstrated that the majority of signal previously attributed to S-nitrosothiols during chemiluminescent detection in the plasma from endotoxaemic cirrhotic rats is mercury stable and is therefore attributed to N-nitrosamine formation. The identity of the mercury stable fraction of NO carrying species in plasma has been partially characterised and found to be carried either on albumin or on an albumin associated molecule. It has also been established that when the conjectured N-nitrosamine is synthesised in vitro and incubated with platelets, it is found to have an inhibitory effect on platelet aggregation similar to that found from S-nitrosothiols. Hypo-reactivity of isolated aortic rings to vasoconstrictors has also been confirmed in the rat model of BDL cirrhosis. However, the injection of cirrhotic rats with lipoic acid (a thiol antioxidant shown to ameliorate the development of the hyperdynamic circulation in the bile duct ligated rat), had no effect on the reactivity of isolated aortic rings as was initially hypothesised. Finally, an adaptation of the Ellman's reaction for analysis of total reduced thiol concentration in plasma was validated and used to assess plasma reduced thiol concentration in cirrhotic rats. It was found that chronic, 25 day bile duct ligation results in a drop in free thiol concentration in the plasma of 75% over sham operated rats.

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