Comparative study on antioxidant effects and vascular matrix metalloproteinase-2 downregulation by dihydropyridines in renovascular hypertension.
The vascular remodeling associated with hypertension involves oxidative stress and enhanced matrix metalloproteinases (MMPs) expression/activity, especially MMP-2. While previous work showed that lercanidipine, a third-generation dihydropyridine calcium channel blocker (CCB), attenuated the oxidative stress and increased MMP-2 expression/activity in two-kidney, one-clip (2K1C) hypertension, no previous study has examined whether first- or second-generation dihydropyridines produce similar effects. We compared the effects of nifedipine, nimodipine, and amlodipine on 2K1C hypertension-induced changes in systolic blood pressure (SBP), vascular remodeling, oxidative stress, and MMPs levels/activity. Sham-operated and 2K1C rats were treated with water, nifedipine 10 mg/kg/day, nimodipine 15 mg/kg/day, or amlodipine 10 mg/kg/day by gavage, starting 3 weeks after hypertension was induced. SBP was monitored weekly. After 6 weeks of treatment, quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin-stained sections. Aortic and systemic reactive oxygen species levels were measured by using dihydroethidine and thiobarbituric acid-reactive substances (TBARs), respectively. Aortic MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Nifedipine, nimodipine, or amlodipine attenuated the increases in SBP in hypertensive rats by approximately 17% (P < 0.05) and prevented vascular hypertrophy (P < 0.05). These CCBs blunted 2K1C-induced increases in vascular oxidative stress and plasma TBARs concentrations (P < 0.05). All dihydropyridines attenuated the increases in aortic MMP-2 levels and activity associated with 2K1C hypertension. These findings suggest lack of superiority of one particular dihydropyridine, at least with respect to antioxidant effects, MMPs downregulation, and inhibition of vascular remodeling in hypertension.
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil.
Diogo M O
DM
Marçal
Elen
E
Rizzi
Alisson
A
Martins-Oliveira
Carla S
CS
Ceron
Danielle A
DA
Guimaraes
Raquel F
RF
Gerlach
Jose E
JE
Tanus-Santos
D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects*; D018093:Gelatinases / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy / Q000188:drug therapy / Q000473:pathology; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology / Q000627:therapeutic use; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000975:Antioxidants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D017311:Amlodipine; D009553:Nimodipine; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D009543:Nifedipine