Lercanidipine reduces matrix metalloproteinase-2 activity and reverses vascular dysfunction in renovascular hypertensive rats.
Increased expression/activity of matrix metalloproteinases (MMPs), especially MMP-2, plays a role in the vascular alterations induced by hypertension, and increased oxidative stress is a major factor activating MMPs. Here, we hypothesized that lercanidipine, a calcium channel blocker, could attenuate the increases in oxidative stress and MMP-2 expression/activity in the two-kidney, one-clip (2K-1C) hypertensive rats. Sham-operated or 2K-1C hypertension rats were treated with lercanidipine 2.5 mg/kg/day (or vehicle) starting three weeks after hypertension was induced. Systolic blood pressure was monitored weekly. After five weeks of treatment, aortic rings were isolated to assess endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall were studied in hematoxylin/eosin sections. Aortic MMP-2 levels were determined by gelatin zymography. Aortic MMP-2/tissue inhibitor of metalloproteinases (TIMP)-2 mRNA levels were determined by quantitative real-time RT-PCR. Plasma thiobarbituric acid reactive substances concentrations were determined using a fluorometric method. Lercanidipine attenuated 2K-1C hypertension (224+/-12 versus 183+/-11 mm Hg in 2K-1C rats and 2K-1C + Lercandipine rats, respectively; P<0.01) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Increased MMP-2 and Pro-MMP-2 levels were found in the aortas of 2K-1C rats (all P<0.05). Lercandipine attenuated 2K-1C-induced increases in MMP-2 by more than 60% and blunted 2K-1C-induced increases in oxidative stress (both P<0.001). While hypertension-induced significant aortic wall hypertrophy and approximately 9-fold increases in the ratio of MMP-2/TIMP-2 mRNA expression (both P<0.05), lercandipine did not affect these changes. These results suggest that lercanidipine produces antihypertensive effects and reverses the endothelial dysfunction associated with 2K-1C hypertension, probably through mechanisms involving antioxidant effects leading to lower MMP-2 activation.
Martinez
Marcio L L
ML
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
Castro
Michele M
MM
Rizzi
Elen
E
Fernandes
Karla
K
Demacq
Caroline
C
Bendhack
Lusiane M
LM
Gerlach
Raquel F
RF
Tanus-Santos
Jose E
JE
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004792:Enzyme Precursors; D017392:Thiobarbituric Acid Reactive Substances; D018093:Gelatinases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; C060343:lercanidipine