title: Inhibition of vascular angiotensin-converting enzyme by telmisartan via the peroxisome proliferator-activated receptor gamma agonistic property in rats.
abstract: The angiotensin receptor blocker (ARB) telmisartan is a partial agonist of peroxisome proliferator-activated receptor gamma (PPARgamma). Typical PPARgamma agonists suppress the gene expression of angiotensin-converting enzyme (ACE) in vascular tissues. However, it remains unclear whether or not PPARgamma activation by telmisartan can inhibit vascular ACE activity. We compared the effects of PPARgamma agonistic telmisartan and non-agonistic valsartan on ACE, vascular function and oxidative stress in stroke-prone spontaneously hypertensive rats (SHR-SP) and in sodium (1% NaCl)-loaded SHR-SP. SHR-SP and sodium-loaded SHR-SP received placebo, 1 mg/kg telmisartan, or 10 mg/kg valsartan for 2 weeks. Systolic blood pressure (SBP) was equally reduced in SHR-SP given either telmisartan or valsartan compared with SHR-SP given placebo. However, neither telmisartan nor valsartan suppressed SBP in sodium-loaded SHR-SP. Acetylcholine induced significantly less vasorelaxation in SHR-SP than in Wistar-Kyoto rats, but telmisartan and valsartan each significantly prevented such vasorelaxation. However, telmisartan significantly attenuated acetylcholine-induced vasorelaxation in sodium-loaded SHR-SP, whereas valsartan did not. Telmisartan significantly attenuated NADPH oxidase subunit p22(phox) gene expression in both SHR-SP and sodium-loaded SHR-SP, whereas valsartan did not. Likewise, telmisartan also significantly attenuated the significantly increased vascular ACE activity in sodium-loaded SHR-SP, whereas valsartan did not. In conclusion, the partial PPARgamma agonist telmisartan might inhibit vascular ACE activity, and result in the prevention of oxidative stress and endothelial dysfunction more effectively than non-agonistic valsartan.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Takatsuki, Japan. pha010@art.osaka-med.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Maki
authors.initials: M
authors.lastname: Kimura
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kirimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakonjo
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology*; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012083:Renin / Q000097:blood; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D013777:Tetrazoles; D014665:Vasodilator Agents; D000804:Angiotensin II; D000068756:Valsartan; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D014633:Valine; D000109:Acetylcholine; D000077333:Telmisartan