Nifedipine activates PPARgamma and exerts antioxidative action through Cu/ZnSOD independent of blood-pressure lowering in SHRSP.
OBJECTIVE
It has been shown that the calcium antagonist nifedipine upregulates superoxide dismutase (SOD). Although the peroxisome proliferator-activated receptor (PPAR) response element is located in the promoter region of Cu/ZnSOD, it remains unclear whether nifedipine upregulates PPARs and inhibits vascular remodeling. We hypothesthized that nifedipine activates PPARgamma, inhibits vascular remodeling, and improves vascular function in hypertension.


METHODS
Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with vehicle, nifedipine, and PPARgamma selective antagonist GW9662 with nifedipine.


RESULTS
Systolic blood pressure in the three SHRSP groups was higher (p <0.01), and the left ventricular weight/body weight ratio was greater (p <0.01) than in the Wistar-Kyoto rat (WKY) group with no differences observed among the three SHRSP groups. In the SHRSP heart, nifedipine significantly inhibited intramyocardial arterial remodeling and perivascular fibrosis, and reduced oxidative stress, while it significantly restored adiponectin and the smooth muscle cell (SMC) phenotype, and selectively restored PPARgamma and Cu/ZnSOD expression/activities to their levels in the WKY rat heart. Furthermore, nifedipine induced a dose-dependent increase in PPARgamma expression in cultured vascular SMCs. These effects of nifedipine were completely abolished by the co-administration of GW9662 with nifedipine. Nifedipine treatment significantly improved acetylcholine-induced relaxation by 27% compared with the vehicle SHRSP group, but it was still significantly impaired by 20% compared with the WKY group.


CONCLUSIONS
Nifedipine may inhibit vascular remodeling and improve vascular function by selective activation of PPARgamma through the activation of Cu/ZnSOD in hypertension.
Hashimoto
Ryo
R
Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Umemoto
Seiji
S
Guo
Fengling
F
Umeji
Kyoko
K
Itoh
Shinichi
S
Kishi
Hiroko
H
Kobayashi
Sei
S
Matsuzaki
Masunori
M
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000627:therapeutic use*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002121:Calcium Channel Blockers; D047495:PPAR gamma; D013481:Superoxides; D013482:Superoxide Dismutase; D009543:Nifedipine