The overall hypothesis behind these studies is that reversal of the vasodilation of end-stage liver disease (ESLD) and the transition to vasoconstriction of post-transplant hypertension is closely related to alterations in endothelial generation of nitric oxide, which will be reflected by changes in levels and compartmental distribution of NO in plasma and red cells. To accomplish this objective, we wish to examine:
Specific Aim No. 1. Changes in plasma and RBC NO during spontaneous variations in blood pressure and peripheral resistance during a 24-hour period in patients with ESLD and four months after liver transplantation. Our hypothesis is that plasma NO levels and partitioning between plasma and RBC will vary in parallel with circadian changes in wall stress induced by changes in arterial pressure.
Specific Aim No. 2. Changes in plasma and RBC NO induced during infusion of excess substrate (L-arginine), which normally leads to systemic and renal vasodilation. Our hypothesis is that L-arginine excess will increase plasma NO levels in ESLD subjects, but will fail to do so in patients with impaired endothelial function, i.e. hypertension after liver transplantation.
Specific aim No. 3: Changes in vasoconstrictor and vasodilator systems affecting blood flow and perfusion, specifically endothelin, prostacyclin and the renin-angiotensin system in relation to changes in plasma and RBC NO. Our hypothesis is that vasodilator effects of NO will be counterbalanced by greater activation of vasoconstrictor systems in ESLD as compared with post-transplant hypertensive patients with impaired endothelial-dependent mechanisms.
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