Tissue angiotensin II: a matter of location

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).

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