Comparative study on antioxidant effects and vascular matrix metalloproteinase-2 downregulation by dihydropyridines in renovascular hypertension

Abstract

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.

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

“…While there is no evidence that methyldopa produces antihypertensive effects by mechanisms involving reduced MMP-2 activity, it has been demonstrated that some calcium channel blockers may affect circulating MMP levels in hypertensive patients [20,34] and down-regulate MMP-2 in the vessels of hypertensive rats [18,19]. Other antihypertensive drugs were also experimentally shown to down-regulate MMP-2 [35], and therefore, it is possible that antihypertensive drugs used to treat hypertensive disorders of pregnancy ameliorate clinical symptoms by decreasing circulating MMP-2.…”

“…While some antihypertensive drugs, including calcium channel blockers may affect MMP activity [18][19][20], no previous study has examined whether MMP-2 polymorphisms affect the therapeutic responses to drugs used in hypertensive disorders of pregnancy.…”

Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy

“…However, they allow maintenance of pregnancy and promote an increased gestational age of delivery, thus decreasing adverse maternal and fetal outcomes. 31 In this respect, while some antihypertensive drugs can downregulate MMPs' activities [32][33][34][35] and as this effect may contribute to the reduction of blood pressure, no previous study had examined whether MMP-9 polymorphisms affect the antihypertensive effects of drugs used to treat hypertensive disorders of pregnancy. In this study, we investigated for the first time the effects of MMP-9 polymorphisms in responsiveness to methyldopa or to total antihypertensive therapy in hypertensive disorders of pregnancy.…”

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

“…Furthermore, a number of drug groups including angiotensin II receptor antagonists [92], diuretics [93], calcium channel blockers [94], statins [95, 96], acetylsalicylic acid [97], and thrombin inhibitors [98] have also been linked to modulate gelatinase activity.…”