A study of blood vessel reactivity in liver cirrhosis

Arm 1 (duration- 4 hours total time required, 2 interventions) Intervention 1- EndoPAT (Itamar, Israel) study to determine the presence and degree of endothelial dysfunction in cirrhosis versus health using this novel non-invasive device. The EndoPAT study takes fifteen minutes and is performed when biosensor pads are placed on the index fingers of both hands. The brachial artery of one arm is occluded using a pressure cuff for five minutes. When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as reactive hyperaemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software providing the EndoPAT index. Intervention 2- Forearm Plethysmography (FP) The brachial artery of the non-dominant arm will be cannulated for the purpose of the FP study. The cannulation will be done with aseptic technique using a 3 French needle under local anaesthesia (1% lignocaine). The cannula will be attached to a pressure transducer and patency maintained with heparinized saline. Blood pressure and heart rate will be monitored closely throughout the study in the non-cannulated arm using an automated blood pressure recorder. Forearm Blood Flow (FBF) will be monitored using the strain gauge applied around the widest aspect of the forearm approximately one third of the way between the elbow and the wrist. The strain gauge is then attached to a plethysmograph which measures it’s degree of stretch. During recordings hand circulation will be excluded from study by inflating a small cuff at the wrist to 250mmHg. A second cuff will be placed on the upper arm and inflated to 45mmHg to occlude venous outflow. These measures will ensure that only the isolated forearm circulation will be studied. FBF will be monitored for 30 minutes prior to drug infusion to ensure a stable baseline. A drug infusion pump will be used to deliver accurate amounts of drug to participants. The following protocol will be followed in all participants (cirrhotic and controls); Drug infusion protocol 1 1) Angiotensin-(1-7) infused intra-arterially for five minutes at each of the following doses over a fifteen minute period ; 100pmol/min, 1,000 pmol/min, 10,000 pmol/min. FBF will be measured in the last 2 minutes of each infusion. 2) 20 minute recovery period. 3) Angiotensin II infused intra-arterially for five minutes at each of the following doses over a fifteen minute period; 3pmol/min, 10pmol/min, 30pmol/min. FBF will be measured in the last 2 minutes of each infusion. 4) 20 minute recovery period. 5) Angiotensin-(1-7) infused intra-arterially for fifteen minutes at 100pmol/min and then continued whilst step 3 repeated 6) 20 minute recovery period. 7) L-NMMA (Nitric oxide synthase inhibitor) infused intra-arterially for fifteen minutes at 4micromol/min and then continued whilst step 1 repeated Arm 2 (duration-2 hour total time required, 2 interventions) Cirrhotic patients within a 1 year post liver transplantation period only will be asked back to undergo a comparative(pre and post liver transplantation) EndoPAT study and FP study (limited drug infusion protocol) Drug infusion protocol 2 (post liver transplant only) 1)Angiotensin-(1-7) infused intra-arterially for five minutes at each of the following doses over a fifteen minute period; 100pmol/min, 1,000 pmol/min, 10,000 pmol/min. FBF will be measured in the last 2 minutes of each infusion.