title: Effect of peroxisome proliferator-activated receptor-alpha and -gamma activators on vascular remodeling in endothelin-dependent hypertension.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptors (PPARs) may modulate in vitro the vascular production of vasoactive peptides such as endothelin-1 (ET-1). Thus, we investigated in vivo the interaction between PPARs and ET-1 in deoxycorticosterone acetate (DOCA)-salt rats that overexpress vascular ET-1.
  
  
  RESULTS
  Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were divided into 4 groups (n=6 each): control group, DOCA-salt group, DOCA-salt+PPAR-gamma activator (rosiglitazone, 5 mg x kg(-1) x d(-1)), or DOCA-salt+PPAR-alpha activator (fenofibrate, 100 mg x kg(-1) x d(-1)). Systolic blood pressure was significantly increased in the DOCA-salt group (240+/-11 vs 121+/-2 mm Hg in Uni-Nx, P<0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172+/-3 mm Hg vs DOCA-salt, P<0.05) but not by fenofibrate. Both PPAR activators abrogated the increase in prepro-ET-1 mRNA content in the mesenteric vasculature of DOCA-salt rats. The media-to-lumen ratio was increased in DOCA-salt rats (10.3+/-0.9% vs 4.9+/-0.5% in Uni-Nx rats, P<0.01). Rosiglitazone and fenofibrate prevented the hypertrophic remodeling observed in DOCA-salt rats without affecting vascular stiffness. Rosiglitazone but not fenofibrate prevented endothelial dysfunction in pressurized mesenteric arteries. Finally, both rosiglitazone and fenofibrate prevented the vascular increase in superoxide anion production induced in DOCA-salt animals.
  
  
  CONCLUSIONS
  PPAR-alpha and -gamma activators were able to modulate endogenous production of ET-1 and had beneficial vascular effects in endothelin-dependent hypertension.
authors.affiliation: CIHR Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Farhad
authors.initials: F
authors.lastname: Amiri
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Lavoie
authors.forename: Quy N
authors.initials: QN
authors.lastname: Diep
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D016232:Endothelins / Q000378:metabolism / Q000502:physiology; D005109:Extracellular Matrix / Q000737:chemistry / Q000473:pathology; D011345:Fenofibrate / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology* / Q000517:prevention & control; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000737:chemistry / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D010100:Oxygen / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D017540:Tunica Media / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D010100:Oxygen; D011345:Fenofibrate