http://repub.eur.nl/res/aut/11060/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/31937/ 2002-06-19T00:00:00Z 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). http://repub.eur.nl/res/pub/13005/ 2002-01-01T00:00:00Z 1. We investigated why angiotensin (Ang) I and II induce vasoconstriction with similar potencies, although Ang I-II conversion is limited. 2. Construction of concentration-response curves to Ang I and II in porcine femoral arteries, in the absence or presence of the AT(1) or AT(2) receptor antagonists irbesartan and PD123319, revealed that the approximately 2 fold difference in potency between Ang I and II was not due to stimulation of different AT receptor populations by exogenous and locally generated Ang II. 3. Measurement of Ang I and II and their metabolites at the time of vasoconstriction confirmed that, at equimolar application of Ang I and II, bath fluid Ang II during Ang I was approximately 18 times lower than during Ang II and that Ang II was by far the most important metabolite of Ang I. Tissue Ang II was 2.9+/-1.5% and 12.2+/-2.4% of the corresponding Ang I and II bath fluid levels, and was not affected by irbesartan or PD123319, suggesting that it was located extracellularly. 4. Since approximately 15% of tissue weight consists of interstitial fluid, it can be calculated that interstitial Ang II levels during Ang II resemble bath fluid Ang II levels, whereas during Ang I they are 8.8 - 27 fold higher. Consequently at equimolar application of Ang I and II, the interstitial Ang II levels differ only 2 - 4 fold. 5. Interstitial, rather than circulating Ang II determines vasoconstriction. Arterial Ang I, resulting in high interstitial Ang II levels via its local conversion by ACE, may be of greater physiological importance than arterial Ang II. http://repub.eur.nl/res/pub/9789/ 2001-01-01T00:00:00Z To investigate the functional consequences of postinfarct cardiac angiotensin (ANG) type 2 (AT(2)) receptor upregulation, rats underwent coronary artery ligation or sham operation and were infused with ANG II 3-4 wk later, when scar formation is complete. ANG II increased mean arterial pressure (MAP) more modestly in infarcted animals than in sham animals. The AT(1) receptor antagonist irbesartan, but not the AT(2) receptor antagonist PD123319, decreased MAP and antagonized the ANG II-mediated systemic hemodynamic effects. Myocardial (MVC) but not renal vascular conductance (RVC) was diminished in infarcted versus sham rats. ANG II did not affect MVC and reduced RVC in all rats. MVC was unaffected by irbesartan and PD123319 in all animals. However, with PD123319, ANG II reduced MVC in sham but not infarcted animals, and, with irbesartan, ANG II increased MVC in infarcted but not sham animals. Irbesartan increased RVC and antagonized the ANG II-mediated renal effects in all animals. RVC, at baseline or with ANG II, was not affected by PD123319 in infarcted and sham animals. In conclusion, coronary but not renal AT(2) receptor stimulation results in vasodilation, and this effect is enhanced in infarcted rats. http://repub.eur.nl/res/pub/9471/ 2000-01-01T00:00:00Z BACKGROUND: The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II). METHODS AND RESULTS: Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, (125)I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during (125)I-Ang I infusion. Ang II type 1 (AT(1)) receptor-mediated uptake of circulating (125)I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT(1) receptor-mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT(1) receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%. CONCLUSIONS: Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT(1) receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT(1) receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.