부산대학교 도서관

The vascular endothelium is intimately related to both the structure and function of blood vessels. Within this thesis, the role of the vascular endothelium in endogenous fibrinolysis is studied. In particular, the relationship of this critical endothelial function to the renin-angiotensin and kallikrein-kinin systems is addressed, as well as the influence of homocysteine and antioxidants. Angiotensin-converting enzyme (ACE) inhibition is known to be beneficial in heart failure and other cardiovascular diseases, and one of the beneficial effects may be a reduction in thrombotic events. Both angiotensin II and bradykinin may play a role in the regulation of endogenous fibrinolysis and both are modified by ACE inhibition, with decreased production of angiotensin II but decreased breakdown of bradykinin. The technique of bilateral forearm plethysmography was utilised to make forearm blood flow measurements, whilst allowing for the venous sampling of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1), not only from an arm infused with vasoactive peptides, but also from the non-infused arm which acts as a contemporaneous control. Studies were performed in healthy volunteers. Firstly, the effects of angiotensin II and bradykinin were studied. Angiotensin II did not affect acute endothelial cell t-PA or PAI-1 release. In contrast, bradykinin is a potent vasodilator and selective stimulus for acute local t-PA release. We went on to study how these effects were modified in healthy volunteers taking quinapril 40 mg daily, losartan 50 mg daily or placebo for the 7 days prior to forearm blood flow studies. We demonstrated a selective and marked augmentation of bradykinin-induced t-PA release during ACE inhibition which was absent during placebo and losartan therapy. These findings suggest that the beneficial clinical and vascular effects of ACE inhibition may in part be mediated through local augmentation of bradykinin-induced t-PA release. Finally, elevated plasma homocysteine measurements are associated with clinical thrombotic events, including myocardial infarction, and it is thought that an oxidative stress may be associated with hyperhomocysteinaemia. We hypothesised that experimental hyperhomocysteinaemia, produced by methionine-loading, would impair substance P-induced forearm vasodilatation and t-PA release. We further hypothesised that vitamin C supplementation might reverse these potential derangements in endothelial function. However, we showed that in healthy volunteers, t-PA release was augmented during methionine-loading and unaffected by vitamin C supplementation. This suggests that the acute endogenous fibrinolytic capacity of the endothelium is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism. Chronic hyperhomocysteinaemia, however, may have very different effects.