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Sauge, Elodie

University of British Columbia

Losartan and telmisartan are blood pressure (BP)-lowering angiotensin II (ANGII) type 1 receptor (AT1) blockers (ARBs) with unexpected therapeutic properties in settings not linked to high BP. ARB pleiotropism is complex, however previous studies have revealed that ARBs can activate endothelial function in vivo by promoting the release of protective vasodilatory nitric oxide (NO) in fashions that may be independent of their ANGII/AT1-blocking effects. As a partial prodrug, losartan is first metabolized into EXP3179, which has traditionally been considered a non-AT1-blocking molecule, followed by conversion into EXP3174, the predominant AT1 blocker. We hypothesized that EXP3179 is the elusive metabolite behind losartan's unexpected NO-activating properties. To test this hypothesis, wild-type and transgenic mice and tissues were treated with losartan, EXP3179 and EXP3174. We showed that contrary to previous beliefs, EXP3179 has similar AT1-blocking and BP-lowering effects as EXP3174, although only the former has the unique ability to enhance endothelial function. We observed that the endothelial function-enhancing effects of EXP3179 were endothelium removal-sensitive, involved the endothelial NO synthase (eNOS) and endothelium-derived hyperpolarizing factor (EDHF) pathways, and are dependent on an intact caveolae/caveolin-1 system, a critical component of the luminal endothelial membrane’s ability to sense flow. As AT1 antagonists did not diminish EXP3179’s effects on vessel reactivity and NO release, ANGII type 2 receptor (AT2) knock-out mice were used to evaluate whether the NO-potentiating effects of losartan and EXP3179 resulted from an ANGII switch towards protective AT2 signalling or direct AT2 activation. We demonstrated that both losartan and EXP3179 act on the endothelium via an AT2-independent mechanism. Finally, we explored the pleiotropic effects of losartan and the most effective ARB at activating the NO pathway, telmisartan, in mouse models of chronic obstructive pulmonary disease (COPD) and allergic asthma. Contrary to previous literature, both drugs failed to improve lung function and remodelling in COPD while showing limited efficacy in improving allergic asthma. In summary, the current thesis provides a better understanding of the complex and diverse pleiotropic properties of ARBs and proposes that direct but selective activation of endothelial function by ARB-like molecules may be behind their protective properties in non-hypertensive settings.

Text

2024-07-08

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88592

Pharmacology and Therapeutics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/