Dokument: Contribution of angiotensin converting enzyme to angiotensin receptor blocker induced angio-oedema

Titel:	Contribution of angiotensin converting enzyme to angiotensin receptor blocker induced angio-oedema
Weiterer Titel:	Der Beitrag des Angiotensin-konvertierenden Enzyms zum Angiotensin-Rezeptorblocker-induzierten Angioödem
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=58435
URN (NBN):	urn:nbn:de:hbz:061-20220117-105941-7
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Fahimi, Ehsan [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 8,49 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 12.01.2022 / geändert 12.01.2022
Beitragende:	Prof. Dr. Kojda, Georg [Gutachter] Prof. Dr. Stark, Holger [Gutachter]
Stichwörter:	angio-oedema, angioedema, angioödem, angiotensin, angiotensin rezeptorblocker, angiotensin converting enzyme, bradykinin, ABRASE
Dewey Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften 500 Naturwissenschaften und Mathematik
Beschreibung:	For decades, angiotensin I (Ang I)-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor type 1 (AT1) blockers (ARBs) have been in use for the treatment of hypertension and heart failure. Non-allergic angio-oedema is a potentially life-threatening side effect of these therapeutics, characterized by subcutaneous swelling of the face, oral cavity, and the larynx, which if untreated is likely to develop into airway obstruction. For ACE inhibitors, impaired degradation of bradykinin and subsequent overactivation of its receptor is thought to be the cause. The cause of ARB-induced angio-oedema is less well understood, yet recent evidence suggests a link between increased Ang II receptor type 2 (AT2) stimulation and decreased bradykinin degradation, which calls for further investigations. The selective AT2 agonist compound 21 (C21) was utilized to investigate the effect of AT2 stimulation on ACE activity in human dermal microvascular endothelial cells (HDMEC) as well as in mouse lungs and plasma. Those mouse samples were used to investigate changes in protein levels of ACE, Ang I and Ang II, as each would reflect changes in altered ACE activity. The Miles assay technique was applied in the dorsal skin of mice to study the effect of AT2 activation on bradykinin-induced extravasation. To investigate possible effects of AT2 stimulation on the circulatory system of mice, on the one hand, blood pressure data were collected and on the other hand, the microcirculation in the earlobe was visualized by two-photon excitation microscopy (TPEM). Finally, several animal studies and a multicentre clinical trial were conducted to further explore the signal transduction mechanisms that lead to the increased dermal extravasation caused by bradykinin. In HDMECs, C21 induced a significant reduction of ACE activity. Results from Miles assays showed that AT2 activation has an enhancing effect on bradykinin-induced extravasation in mouse skin. This effect was abolished in AT2 knockouts and under simultaneous AT2 inhibition. There was no correlation between AT2 activation and systolic blood pressure in mice. However, a direct effect on the dermal microcirculation cannot be excluded, thus further optimisation of TPEM is required for clarification. Lung snippets incubated with C21 and assayed for ACE activity showed slightly decreased ACE activity, whereas in the corresponding supernatants ACE activity was significantly increased. In mice treated with C21, a dose-dependent increase in ACE activity was observed in plasma but not in lung lysates. Western blot analysis of ACE protein content in lung lysates of mice previously treated with C21 revealed a significant reduction of ACE protein content. Immunological approaches using the ELISA technique and Dynabeads did not demonstrate increased ACE levels in corresponding plasma samples. Furthermore, treatment of mice with C21 had no effect on plasma Ang I and Ang II levels. Studies in mice showed that B2 activation does not involve activation of endothelial nitric oxide synthase but rather activation of cyclooxygenases (COX). The nonselective COX inhibitor diclofenac significantly inhibited bradykinin-induced dermal extravasation. A similar, albeit smaller, effect was observed in human volunteers receiving an intradermal injection of bradykinin after the intake of ibuprofen. Overall experimental data suggest a contribution of AT2 to non-allergic bradykinin-induced angio-oedema. The significantly increased bradykinin-induced extravasation in the skin of mice pre-treated with C21, suggests a locally impaired bradykinin degradation. Some experimental approaches failed to show systemic effects of AT2 activation on ACE activity, suggesting that a putative effect was offset by the involvement of different vascular beds with each having different responses at the local level. However, AT2 stimulation was also shown to modulate ACE activity both in-vitro and in-vivo, presumably through a shedding mechanism in which membrane-bound ACE is converted to a soluble, circulating form with reduced catalytic activity. This phenomenon might lead to an increased local concentration of bradykinin with overactivation of its receptor, eventually leading to the clinical manifestations of bradykinin-induced angio-oedema. Separate studies investigating the downstream bradykinin signalling pathway demonstrated the contribution of COX activity to bradykinin-induced dermal extravasation in mouse models and humans. This finding may provide a rationale for pharmacological inhibition of arachidonic acid metabolism, which is the substrate of COX.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Medizinische Fakultät » Institute » Institut für Pharmakologie und Klinische Pharmakologie
Dokument erstellt am:	17.01.2022
Dateien geändert am:	17.01.2022
Promotionsantrag am:	04.08.2021
Datum der Promotion:	14.12.2021