thesis
Tissue angiotensin II: a matter of location
- Publication date
- 19 June 2002
- Publisher
- Whether cardiac Ang IT generation occurs in an auto-, para-, or intracrine manner as well as
whether Ang II stimulation of the AT 2 receptor mediates vasodilation, has not yet been
thoroughly investigated. Therefore, we performed in-vivo studies in rats and pigs and in-vitro
studies in porcine isolated vessels with the following aims:
1. To study the vasoactive role of AT2 receptors under normal and pathological conditions,
as well as to investigate which vasodilator compounds counterbalance Ang II -mediated
vasoconstriction.
2. To determine the site oflocal Ang II formation, and the enzyme(s) (ACE and/or chymase)
involved in its generation.
To address issue 1, we made use of the radioactive nricrosphere method under various
conditions, which allowed us to measure blood flow in all organs of one animal. In normal
anesthetized rats, blood flow was measured during Ang IT infusion in the absence or presence
of antagonists at AT1 or ATz receptors (chapter 2) and following inhibition of nitric oxide
synthase or cyclooxygenase (chapter 3 ). Shnilar studies were performed in rats 4 weeks after
coronary artery ligation, i.e, at the time when ATz receptors are upregulated (chapter 4). To
address issue 2, a detailed analysis of cardiac angiotensin generation was made in myocardial
infarcted pigs with and without RAS blockade (chapter 5). Interstitial Ang I and Ang II levels
were measured in porcine hearts in vivo, using the microdialysis technique, (chapter 6) and in
isolated porcine arteries (chapters 7). Finally, the enzyme responsible for interstitial
Ang I-to-Ang ll conversion was determined using a modified version of the rat Langendorff
heart, which allows separate collection of coronary effluent and interstitial fluid (chapter 8).