Local renin-angiotensin systems

The aim of this thesis was twofold. First, the regional metabolism and production of angiotensin I and angiotensin U were quantified in vivo in man and in anesthetized pigs. This was done by giving constant infusions of radiolabelect J25J-angiotensin I into either a peripheral vein (man) or into the left cardiac ventricle (pig). Blood samples were taken under steady state conditions from various arterial and venous sampling sites. By measuring in each sample the levels of intact radiolabelect angiotensin I and angiotensin U and of endogenous angiotensin I and angiotensin II one can calculate both the degree of regional metabolism of angiotensin I and angiotensin II and the amount of angiotensin I and angiotensin II that is generated in a certain vascular bed. Additional measurements of plasma renin activity (PRA) and calculations of the regional conversion of 125I-angiotensin I to 125I-angiotensin TI make it possible to calculate the amount of locally generated angiotensin I that can be attributed to the action of circulating renin on circulating renin substrate and the amount of locally generated angiotensin U that can be accounted for by regional conversion of arterially delivered angiotensin I. Our data show clearly that part of angiotensin I in plasma is produced locally, probably in vascular tissue, and not in circulating plasma by PRA, and that most of the renin responsible for this local production is kidney-derived. Part of circulating angiotensin U also appeared to be produced locally, independent of plasma angiotensin I. The second aim of this thesis was to investigate the existence of a local reninangiotensin system in the eye. This was done based upon previous findings in diabetic subjects (33), which showed that a relationship existed between the high plasma prorenin levels and the presence of retinopathy, especially the proliferative type, in these subjects. Oenlarfluid samples obtained from human subjects (both diabetic and non-diabetic) during eye surgery were examined for this purpose. Additionally, angiotensin and renin/prorenin measurements were performed in oenlar tissue extracts from both cows and pigs. Human vitreous and subretinal fluid were found to contain prorenin levels too high to be explained by leakage from plasma only. This was not the case with angiotensinogen, angiotensin I or angiotensin II in these oenlar fluids. Renin levels were in the low to undetectable range. In contrast, angiotensin I, angiotensin II, renin and prorenin levels in bovine and porcine oenlar tissues were far too high to be explained by the presence of plasma in these tissues only. It seems therefore that indeed the eye contains its own renin-angiotensin system. The only component of the oenlar renin-angiotensin system which is being released from the tissues into the vitreous fluid appears to be prorenin. Since prorenin was twofold higher in vitreous fluid obtained from eyes affected by proliferative diabetic retinopathy than in vitreous fluid from eyes of non-diabetic patients, one may hypothesize that the renin-angiotensin system is involved in the development of diabetic retinopathy. The final proof for the existence of an intraoenlar renin-angiotensin system was obtained by the demonstration of renin-, angiotensinogen- and ACE-mRNA expression in humaneyes by the polymerase chain reaction.

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