Assessment of hypoxia and hepatic metabolism in cirrhotic rats using NMR [ 2000 - 2002 ]

Research Grant

Researchers: Prof Allan Mclean (Principal investigator)

Brief description Liver function and hepatic drug metabolism are impaired in patients with cirrhosis but there is currently no adequate explanation to account for this. As a direct consequence, there is no useful therapy beyond liver transplantation. We propose studies aimed at confirming a hypothesis on the mechanisms underlying the development of cirrhosis. From this mechanistic hypothesis, a testable therapeutic hypothesis has been derived. Our primary mechanistic hypothesis is that cirrhosis is associated with reduced oxygen delivery from the blood supply into the liver due to a process known as capillarisation (i.e., The Oxygen Limitation Theory). It is proposed that this reduced oxygen availability leads to impairment of liver function. The major aim of this research project is to confirm or refute the presence of intracellular hypoxia (i.e., decreased oxygen in cells) using nuclear magnetic resonance (NMR) techniques and cirrhotic rats. The nature of any metabolic disturbances or changes in cellular components resulting from intracellular hypoxia will then be characterised. The project will also aim to confirm the impairment of oxygen-dependent drug metabolism in cirrhosis by using NMR to measure the degradation or elimination of a fluorinated drug. Our hypothesis for therapy is that intracellular hypoxia may be reversed, and global liver function improved, by oxygen supplementation and-or an increase in hepatic arterial flow by using oral hepatic arterial vasodilators. Vasodilators exert their action by direct relaxation of blood vessels or by blocking the action of vasoconstrictors. Vasodilators that act solely on the hepatic artery and their influence upon blood pressure will be studied using treated rat livers so that such vasodilators can be tested for their ability to modify liver function in cirrhotic rats in vivo. The ultimate goal will be to carry these observations into studies in normal healthy volunteers and cirrhotic patients in the future.

Funding Amount $AUD 355,341.10

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant