Wirkung von Angiotensin II auf Entzündungsmediatoren bei gesunden Probanden

Hintergrund: Bei der Entstehung atherosklerotischer Gefäßveränderungen spielen Entzündungsreaktionen, die durch Zytokine vermittelt werden, eine zentrale Rolle. Zahlreiche experimentelle Studien legen einen Zusammenhang zwischen dem Renin-Angiotensin-Aldosteron-System und der Zytokinfreisetzung aus dem Endothel nahe. Diese Studie untersucht die Wirkung von exogenem Angiotensin II auf die Zytokinfreisetzung bei gesunden Probanden.

Methoden: Neun gesunde Probanden erhielten Angiotensin II-Infusionen in Dosen von 1, 3 und 10 ng kg^-1 min^-1, jeweils über 45 Minuten, einmal mit und einmal ohne vorherige orale Gabe eines AT₁-Rezeptorantagonisten (160 mg Valsartan). Der arterielle Blutdruck wurde oszillometrisch in 5-minütigen Abständen gemessen. Die Blutabnahme für die Bestimmung der Plasmareninaktivität, des Angiotensin II und des Aldosterons sowie der proinflammatorischen Zytokine Tumornekrosfaktor (TNF)-α, Interleukin (IL)-6 und des Gefäßzelladhäsionsmoleküls (VCAM)-1 erfolgte vor Infusionsbeginn, am Ende jeder Infusionsperiode und eine Stunde nach Infusionsende.

Ergebnisse: Die Angiotensin II-Konzentrationen im Plasma stiegen unter der Infusion von 14,7 ± 16,5 pg ml^-1auf 200,1 ± 127,2 pg ml^-1 an (p < 0,001). Eine Stunde nach Infusionsende lag die Plasmakonzentration von Angiotensin II wieder im Bereich der Basalwerte (16,3 ± 24,8 pg ml^-1). Angiotensin II erhöhte den systolischen und diastolischen Blutdruck von 121 ± 9/70 ± 6 mmHg auf maximal 146 ± 6/97 ± 3 mmHg (p < 0,001). Durch Vorbehandlung mit dem AT₁-Rezeptorantagonisten wurde der Blutdruckanstieg verhindert. Weder unter der Infusion von Angiotensin II noch unter gleichzeitiger Gabe des AT₁-Antagonisten veränderten sich die zirkulierenden Plasmaspiegel von TNF-α, IL-6 und des VCAM-1.

Folgerung: Erhöhte zirkulierende Plasmaspiegel von Angiotensin II induzieren bei gesunden Probanden einen signifikanten Anstieg des arteriellen Blutdrucks, führen jedoch nicht zu kurzfristigen Änderungen der Plasmaspiegel der Zytokine TNF-α, IL-6 und des VCAM-1. Unsere Ergebnisse an gesunden Probanden ziehen das Konzept in Zweifel, dass Angiotensin II, zumindest kurzfristig, Blutdruck-unabhängige Wirkungen über Veränderungen der in der vorliegenden Studie untersuchten Zytokine vermittelt.

Background and objective: Inflammatory reactions mediated by cytokines play a central role in the development of atherosclerotic vascular changes. Numerous experimental studies have suggested a connection between the renin-angiotensin-aldosterone system and cytokine liberation from endothelium. This study investigated the effect of exogenous angiotensin II on cytokine liberation in healthy subjects.

Methods: Nine healthy men, aged 25-28 years, having given informed consent, were given angiotensin II infusions of 1, 3 and 10 ng/kg/min, each time over 45 min, once with and once without preceding oral intake of an AT₁-receptor antagonist (160 mg valsartan). Arterial blood pressures were measured oscillometrically every 5 min. Blood was taken at the end of each perfusion period and one each after its end, measurements being made of plasma activity of angiotensin II, aldosterone, and the pro-inflammatory cytokines tumor necrosis factor (TNK)-α, interleukin (IL)-6, and the vascular cell adhesion molecule (VCAM)-1.

Results: Plasma angiotensin II concentrations during perfusion rose from 14,7 ± 16,5 pg/ml to 200.1 ± 127,2 pg/ml (p< 0.001). The plasma conentrations of angiotensin II were again within the basal range (16.3 ± 24.8 pg/ml) one hour after the end of perfusion. Angiotensin II raised the systolic and diastolic blood pressure from 121 ± 9/70 ± 6 mmHg to a maximum of 146 ± 6/97 ± 3 mmHg (p<0.001). This blood pressure rise was prevented by prior administration of the AT₁-receptor antagonist. Neither the angiotensin II infusion nor the simultaneous administration of AT₁-antagonist altered the circulating plasma level of TNF-α, IL-6 or VCAM-1.

Conclusion: Increased circulating plasma levels of angiotensin II induce a significant rise in arterial pressure of healthy male subjects, but do not in the short therm produce a change in the plasma levels of the cytokines TNF-α, IL-6 and VCAM-1. These results in healthy subjects throw doubt on the hypothesis that, at least in the short term, the effect of angiotensin II on changes in those cytokines measured in this study are independent of the blood pressure.

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