Role of Oxidative Stress in the Development of Vascular Injury and its Therapeutic Intervention by Nifedipine

Abstract

Dihydropyridine-based calcium antagonists (DHPs) are widely used drugs for the treatment of hypertension and angina pectoris. We, along with others, have recently found that nifedipine, one of the most widely used DHPs, inhibits apoptotic cell death of endothelial cells (ECs) as well as vascular inflammation and subsequently improves endothelial function in patients with cardiovascular risk factors, including hypertension and/or diabetes, thus slowing the development and progression of atherosclerosis in these patients. Several papers have suggested that nifedipine exerts beneficial metabolic effects in vivo through its anti-inflammatory properties as well. However, the underlying molecular mechanisms for the cardiometabolic actions of nifedipine remain to be elucidated, because ECs do not possess voltage-operated L-type calcium channels. Meanwhile, we have very recently found that Bay w 9798, a dihydropyridine structurally related to nifedipine with no calcium antagonistic ability, has anti-oxidative and anti-inflammatory properties in vitro. In this paper, we review the role of oxidative stress in the development of vascular injury, especially focusing on the relationships between advanced glycation end products-receptor system, oxidized low-density lipoprotein and tumor necrosis factor-alpha and vasculopathy. We further discuss the potential clinical utility of anti-oxidative properties of nifedipine on various cardiometabolic disorders.

Nifedipine Improves Endothelial Function

“…However, nifedipine had no effects on these expression levels (data not shown). Taking our results and the results of Yamagishi et al 22,36 together, this suggests that nifedipine may exert its antioxidant and corresponding effects on EPCs through attenuation of reduced nicotinamideadenine dinucleotide phosphate oxidase activity in EPCs as in the endothelium. 38 There are several limitations in the present clinical study.…”

“…), is considerably involved in endothelial dysfunction in hypertension. 33 34 Yamagishi et al 22,36 demonstrated that nifedipine directly abrogated vascular reduced nicotinamide-adenine dinucleotide phosphate oxidase activity in endothelial cells. On the other hand, it has been demonstrated that the expression level of antioxidant enzymes is remarkably higher in EPCs compared with mature endothelial cells, which contributes to endogenous tolerance against oxidative stress.…”

Antioxidant Effects of Photodegradation Product of Nifedipine

“…In these experiments, we chose HUVECs because of endothelial cell dysfunction leads to the development of atherosclerosis, and it is known that nifedipine has pleiotropic effects on these cells. 37) Apparent EPR signals of NO-NIF radicals appeared after 10 min incubation, then gradually increased for 6 h, and were maintained for 24 h. Because the shape of the EPR signal of NO-NIF radicals was not symmetrical, as shown in Fig. 3, but asymmetrical, it was evident that the NO-NIF radical species was located in the membrane environment.…”

“…In addition to its hypotensive and anti-anginal effects, pleiotropic effects of nifedipine were recently reported: antiapoptotic and anti-inflammatory effects on endothelial cells that control the development and progression of atherosclerosis. 1,[6][7][8][9][10][11][37][38][39][40][41] However, it is not clear how nifedipine exerts these pleiotropic effects because its antioxidative activity, which is responsible for the cardiovascular protective effect, 13,14,42) is weak in comparison to other DHPs. [43][44][45][46] Incidentally, nifedipine is light-sensitive, and is converted completely to its nitroso analog, 2,6-di-methyl-4-(2-nitrosophenyl)-3,5-pyridine-carboxylic acid dimethyl ester (NO-NIF, Fig.…”

Nifedipine increases energy expenditure by increasing PGC-1α expression in skeletal muscle

“…Nifedipine treatment reduces atherosclerotic plaques in cholesterol-fed rabbits, 2,3 and suppresses development and progression of atherosclerosis in hypertensive patients. 4,5 Nifedipine has recently been reported to have pleiotropic effects on endothelial cells, 6,7 cardiac muscle cells, 8,9 mesangial cells [10][11][12] and neurons, 13,14 through mechanisms independent of blocking Ca channels. Previous studies have reported that nifedipine treatment decreases body weight in obese hypertensive humans 15 and rat models.…”