Angiotensin II Type 1 Receptor Blockade Does Not Enhance Apoptotic Cell Death During Ischemia and Reperfusion in Humans In Vivo

Abstract

Despite the theoretical benefits, angiotensin II type 1 receptor antagonists seem to enhance rather than reduce morbidity and mortality after myocardial infarction compared with angiotensin-converting enzyme inhibitors. This may result from unopposed angiotensin II type 2 receptor stimulation, which is associated with enhanced apoptotic cell death and increased infarct size. We studied whether the clinical effectiveness of irbesartan is hampered by enhanced apoptotic activity, detected by exposition of phosphatidylserines, during ischemia and reperfusion in humans in vivo. Twenty healthy male volunteers were randomized to a 1-week treatment with irbesartan (300 mg/d) or placebo in a double-blind fashion. After treatment, all participants underwent 10 minutes of ischemic exercise of the nondominant forearm. Upon reperfusion, Tc-99m-labeled Annexin A5 was administered, and 1 and 4 hours afterward, both hands were scanned using a gamma camera. Targeting of annexin A5, expressed as the percentage difference in radioactivity in the area of interest (thenar muscle) between experimental and control hand, did not differ between participants treated with irbesartan or placebo. Therefore, irbesartan does not enhance phosphatidylserine exposition in humans in vivo. The results of this study do not support enhanced apoptotic activity after treatment with irbesartan in a setting of ischemia and reperfusion.

Suppressive Effects of Irbesartan on Inflammation and Apoptosis in Atherosclerotic Plaques of apoE−/− Mice: Molecular Imaging with 14C-FDG and 99mTc-Annexin A5

“…This may result from unopposed AT2 receptor stimulation, which is associated with enhanced cell apoptosis. By apoptosis imaging with 99m Tc-annexin A5, Meijer et al demonstrated that irbesartan does not induce apoptosis in transient ischemia-reperfusion in humans [22]. A recent animal study indicated that irbesartan can ameliorate the myocardial ischemia/reperfusion injury via down-regulation of apoptosis [23].…”

Annexin V Imaging Detects Diabetes-Accelerated Apoptosis and Monitors the Efficacy of Benfotiamine Treatment in Ischemic Limbs of Mice

“…The presence of diabetes is believed to impair adequate tissue response to ischemia and further promote apoptotic cell death. 10,11 Our results showed that intravenously administered AnxV-SAv-PEcy5.5 accumulated in greater amounts in ischemic limbs of diabetic compared to nondiabetic mice. This was associated with an increased promotion of apoptosis in ischemic limbs by diabetes, as shown by greater TUNEL staining and caspase-3 activation.…”

Detecting retinal cell stress and apoptosis with DARC: Progression from lab to clinic

“…However, in 2014, Advanced Accelerator Applications began producing GMP 99mTc-rhAnnexin V-128 kits which have since been in clinical trials (NCT02182609, NCT02677714, NCT02667457, NCT03232580, NCT02978885). (Hofstra et al, 2000) (Narula et al, 2001) (Belhocine et al, 2002) (Boersma et al, 2003) (Kemerink et al, 2003) ( Van de Wiele et al, 2003) (Lahorte et al, 2003) (Thimister et al, 2003) (Kartachova et al, 2004) (Kietselaer et al, 2004) (Vermeersch et al, 2004c) (Vermeersch et al, 2004a) (Vermeersch et al, 2004b) (Haas et al, 2004) (Rongen et al, 2005) (Lampl et al, 2006) (Lorberboym et al, 2006) (Kartachova et al, 2006) (Kartachova et al, 2007) (Kietselaer et al, 2007) (Van Den Brande et al, 2007) (Kartachova et al, 2008) (Kurihara et al, 2008) (Hoebers et al, 2008) (Meijer et al, 2009) (Meijer P. et al, 2011) (Meijer et al, 2009) (Engbersen et al, 2012) (Massalha et al, 2018) (Massalha et al, 2018)…”