title: Telmisartan suppresses cerebral injury in a murine model of transient focal ischemia.
abstract: The beneficial effects of angiotensin II type 1 (AT1) receptor blockers (ARB) in cerebrovascular disease have been shown in clinical trials. However, the effects of ARBs vary based on their unique pharmacologic properties. In this study, we focused on telmisartan, a fat-soluble ARB with selective peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist activity, and investigated its effects on ischemic injury in cerebral vasculature using murine models of both transient and permanent focal ischemia. Analysis by triphenyltetrazolium-staining revealed that pre-treatment of mice with telmisartan reduced stroke volume 72 h after the transient ischemic insult in a dose-dependent manner, though such treatment did not reduce stroke volume due to permanent ischemia. Transient ischemia induced pro-inflammatory adhesion molecules, such as ICAM-1 and P-selectin in the ischemic region, and treatment with telmisartan diminished the expression of these adhesion molecules with diminished infiltration of inflammatory cells. The beneficial effect of telmisartan was attenuated, in part, by administration of a PPAR gamma antagonist. Treatment with valsartan (an ARB without PPAR gamma agonist activity) also decreased ischemic injury after transient ischemia, though to a lesser extent than telmisartan. Our findings indicate that telmisartan has a beneficial effect in a murine model of ischemia/reperfusion injury through blockade of AT1 receptors, and, in addition, due to a positive effect via its specific anti-inflammatory PPAR gamma agonist activity.
authors.affiliation: Department of Cerebrovascular Disease, National Cardiovascular Center, Osaka, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Taguchi
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Uno
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakano
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagomi
authors.forename: Haruka
authors.initials: H
authors.lastname: Hirose
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuyama
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors; D044140:Receptor, Angiotensin, Type 1; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan