1. Effect of peroxisome proliferator-activated receptor-alpha and -gamma activators on vascular remodeling in endothelin-dependent hypertension.
- Author
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Iglarz M, Touyz RM, Amiri F, Lavoie MF, Diep QN, and Schiffrin EL
- Subjects
- Animals, Blood Pressure drug effects, Blood Pressure physiology, Body Weight physiology, Endothelin-1 metabolism, Endothelins metabolism, Endothelins physiology, Extracellular Matrix chemistry, Extracellular Matrix pathology, Fenofibrate pharmacology, Hypertension prevention & control, In Vitro Techniques, Male, Mesenteric Arteries chemistry, Mesenteric Arteries drug effects, Oxygen metabolism, Protein Precursors metabolism, Protein Precursors physiology, RNA, Messenger metabolism, RNA, Messenger physiology, Rats, Rats, Inbred Dahl, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear metabolism, Rosiglitazone, Thiazoles pharmacology, Transcription Factors metabolism, Tunica Media chemistry, Tunica Media drug effects, Tunica Media pathology, Tunica Media physiopathology, Vascular Resistance drug effects, Vascular Resistance physiology, Vasodilator Agents pharmacology, Endothelin-1 physiology, Hypertension metabolism, Hypertension physiopathology, Mesenteric Arteries pathology, Mesenteric Arteries physiopathology, Receptors, Cytoplasmic and Nuclear physiology, Thiazolidinediones, Transcription Factors physiology
- 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., Methods and 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.
- Published
- 2003
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