Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-02

Bei einer Vielzahl von kardiovaskulären Erkrankungen, wie der Arteriosklerose, kommt es zur Aktivierung des Renin-Angiotensin-Aldosteron-Systems und einer steigenden Konzentration von Angiotensin II im Plasma. Ein weiteres Kennzeichen, z.B. bei der Herzinsuffizienz, ist die reduzierte Belastungstoleranz, die mit einer verminderten Skelettmuskelfunktion einhergeht. In dieser Studie wurden Untersuchungen an Skelettmuskeln von ApoE-knockout-Mäusen durchgeführt, die als Tiermodell für kardiovaskuläre Erkrankungen dienen. Als etabliertes Modell ist es durch das Fehlen von ApoE und die damit erhöhte Konzentration an Lipoproteinen charakterisiert, was für die Pathophysiolo-gie von kardiovaskulären Krankheiten von Bedeutung ist. Ziel der Studie war es, den Einfluss von Angiotensin II auf die metabolischen Veränderungen an der Skelettmuskulatur und auf die Skelettmuskelfunktion sowie die damit einhergehenden molekularen Veränderungen zu untersuchen. Des Weiteren wurde der Einfluss von zusätzlichem Ausdauertraining analysiert. Hauptaugenmerk wurde dabei auf die Erfassung von Veränderungen des metabolischen Profils in definierten Fasertypen (SO, FOG, FG) mittels Zytophotometrie gelegt. Es wurde die fasertypspezifische glykolytische und oxidative Enzymaktivität mittels Zytophotometer und im Muskelhomogenat gemessen. Eine Muskelfaseranalyse wurde durchgeführt. Weiterhin erfolgte die Untersuchung von funktionellen Veränderungen im Skelettmuskel nach Angiotensin II-Infusion und nach zusätzlichem Ausdauertraining. Ferner wurde der Beitrag von IGF-1 quantitativ erfasst. In dieser Studie konnte zum ersten Mal gezeigt werden, dass sich Faserzusammensetzung und Metabolismus der Skelettmuskulatur unter Angiotensin II-Gabe verändern. Durch Ausdauertraining werden diese Alterationen abgemildert bzw. rückgängig gemacht, was auf einen positiven Effekt von Ausdauertraining auf die Muskelfunktion schließen lässt.

Vasodilator and vasodepressor properties of angiotensins have been reported, and mediation by prostaglandins or nitric oxide has been proposed. Other studies indicate that angiotensin AT2 receptors might mediate a depressor action, and the present study was designed to delineate and explore this possibility in a conscious rabbit model. Large intravenous boluses of angiotensin III (15 nmol/kg) produced a predictable pressor peak (82±4 mm Hg) followed by a depressor phase (20±3 mm Hg), whereas equipressor doses of angiotensin II were less effective at producing depressor responses. Angiotensin-(1-7) did not exert a depressor action, and the reduced potency of angiotensin IV (relative to angiotensin III) was similar for both the pressor and depressor phases (≈100-fold). It is clear that specific angiotensin IV or angiotensin-(1-7) receptors do not mediate depressor effects in this model. The AT1 antagonist losartan (1 mg/kg) blocked both the pressor and depressor components of the angiotensin III response, whereas the AT2 antagonist PD 123319 (35 mg/kg) had no effect on either element of the response. The data obtained with the angiotensin receptor subtype-selective compounds, losartan and PD 123319, suggest that the depressor action is an AT1-mediated effect and give no indication that AT2 receptors could be involved. Paradoxically, the greater potency of angiotensin III as a vasodepressor belies the conclusion that the response is AT1-mediated, because AT1 receptors have a greater affinity for angiotensin II versus angiotensin III.

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1. We studied the effect of intracellular angiotensin II (Ang II) and related peptides on rat aortic contraction, whether this effect is pharmacologically distinguishable from that induced by extracellular stimulation, and determined the Ca2+ source involved. 2. Compounds were delivered into the cytoplasm of de-endothelized aorta rings using multilamellar liposomes. Contractions were normalized to the maximum obtained with phenylephrine (10-5 M). 3. Intracellular administration of Ang II (incorporation range: 0.01-300 nmol mg-1) resulted in a dose-dependent contraction, insensitive to extracellular administration (10-6 M) of the AT1 receptor antagonist CV11947, the AT2 receptor antagonist PD 123319, or the non-selective AT receptor antagonist and partial agonist saralasin ([Sar1,Val5,Ala8]-Ang II (P < 0.05). 4. Intracellular administration of CV11947 or PD 123319 right shifted the dose-response curve about 1000 fold or 20 fold, respectively. PD 123319 was only effective if less than 30 nmol mg-1 Ang II was incorporated. 5. Contraction was partially desensitized to a second intracellular Ang II addition after 45 min (P < 0.05). 6. Intracellular administration of Ang I and saralasin also induced contraction (P < 0.05). Both responses were sensitive to intracellular CV11947 (P < 0.05), but insensitive to PD 123319. The response to Ang I was independent of intracellular captopril. 7. Contraction induced by extracellular application of Ang II and of Ang I was abolished by extracellular pre-treatment with saralasin or CV11947 (P < 0.05), but not with PD 123319. Extracellular saralasin induced no contraction. 8. Intracellular Ang II induced contraction was not affected by pre-treatment with heparin filled liposomes, but completely abolished in Ca2+-free external medium. 9. These results support the existence of an intracellular binding site for Ang II in rat aorta. Intracellular stimulation induces contraction dependent on Ca2+-influx but not on Ins(1,4,5)P3 mediated release from intracellular Ca2+-stores. Intracellular Ang I and saralasin induce contraction, possibly via the same binding site. Pharmacological properties of this putative intracellular receptor are clearly different from extracellular stimulated AT1 receptors or intracellular angiotensin receptors postulated in other tissue.

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