title: 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.
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Meijer
authors.forename: Constantijn W
authors.initials: CW
authors.lastname: Wouters
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Scheffer
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
mesh_terms: D000293:Adolescent; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects* / Q000627:therapeutic use; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D015444:Exercise; D005542:Forearm; D006225:Hand / Q000098:blood supply / Q000000981:diagnostic imaging; D006801:Humans; D000077405:Irbesartan; D007511:Ischemia; D019194:Ischemic Preconditioning; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D010718:Phosphatidylserines / Q000378:metabolism; D011877:Radionuclide Imaging; D015427:Reperfusion Injury / Q000000981:diagnostic imaging / Q000517:prevention & control*; D013667:Technetium; D013777:Tetrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D017304:Annexin A5; D001713:Biphenyl Compounds; D010718:Phosphatidylserines; D013777:Tetrazoles; D013667:Technetium; D000077405:Irbesartan