Studies of the renin angiotensin system in the human vasculature
The work presented in this thesis concentrates on the local generation of AII. Preliminary experiments using wire myography were performed in human resistance arteries from normal subjects, obtained by subcutaneous gluteal at biopsy. In these vessels, AI stimulated a contractile repose that was dependent on activation of the AII type 1 receptor (ATIR). Thus, conversion of AI to AII can occur within the vasculature. This conversion was resistant to inhibition of ACE with enalaprilat in human tissue. In contrast, AI responses in rabbit arteries were almost completely inhibited by enalaprilat. Further investigation demonstrated that the combination of enalaprilat and the chymase inhibitor, chymostatin (but neither agent alone), inhibited the response to AI in human resistance arteries. Thus, a dual pathway for AII generation exists in human arteries, probably mediated by ACE and chymase. Since the significance of non-ACE AII generation may be greatest in patients taking ACE-inhibitors, further studies were conducted on resistance arteries from patients with chronic heart failure (CHF) who were receiving such medication, compared to patients with coronary heart disease (CHD). In patients with CHD a similar dual pathway to that observed in normal volunteers appeared to be present. However, in arteries from patients with CHF, the contribution of chymase to AII generation - as inferred from the effect of inhibiting ACE - appeared to be less. Thus, the activity of the enzymes responsible for AII generation may be modulated by either the syndrome, or its treatment.