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.

01 Nov 2007·Journal of International Medical ResearchQ4 · MEDICINE

Bay w 9798, a Dihydropyridine Structurally Related to Nifedipine with No Calcium Channel-blocking Properties, Inhibits Tumour Necrosis Factor-α-induced Vascular Cell Adhesion Molecule-1 Expression in Endothelial Cells by Suppressing Reactive Oxygen Species Generation

Q4 · MEDICINE

ArticleOA

Author: Nakamura, K ; Yamagishi, S ; Inoue, H ; Matsui, T

Dihydropyridine-based calcium antagonists (DHPs) are widely used to treat hypertension. We have previously shown that nifedipine, one of the most popular DHPs, blocks tumour necrosis factor-α (TNF-α)-induced monocyte chemoattractant protein-1 as well as vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells by suppressing reactive oxygen species generation (ROS). The molecular mechanism is still to be elucidated, however, because endothelial cells do not possess voltage-operated L-type calcium channels. The aim of this study was to determine in TNF-α-exposed human umbilical vein endothelial cells (HUVECs) whether and how Bay w 9798, a dihydropyridine structurally related to nifedipine with no calcium antagonistic properties, may suppress VCAM-1 expression, a key molecule which mediates the adhesion of monocytes to vasculature in the early stages of atherosclerosis. In HUVECs, 10 ng/ml TNF-α for 4 h stimulated ROS generation and subsequently upregulated VCAM-1 mRNA levels, both of which were dose-dependently blocked by Bay w 9798. The results demonstrated that Bay w 9798 inhibited VCAM-1 expression in TNF-α-exposed cells by suppressing ROS generation. They suggest that the anti-inflammatory and anti-oxidative properties of nifedipine and Bay w 9798 may be ascribed to the dihydropyridine structure, which is common to both molecules and has no calcium antagonistic ability.

01 Mar 2000·British Journal of PharmacologyQ2 · MEDICINE

Modulation by dihydropyridine‐type calcium channel antagonists of cytokine‐inducible gene expression in vascular smooth muscle cells

Q2 · MEDICINE

Article

Author: Rolf Wachter ; Marco Cattaruzza ; Andreas H Wagner ; Markus Hecker

The 1,4‐dihydropyridine nifedipine is frequently used in the therapy of hypertension and heart failure. In addition, nifedipine has been shown to exert distinct anti‐arteriosclerotic effects both in experimental animal models and in patients. In the present study we have investigated the hypothesis that the latter effect of this class of drugs is mediated by an interference with the expression of pro‐arteriosclerotic gene products in the vessel wall. Moreover, to elucidate as to whether nifedipine acts via L‐type calcium channel blockade, its effects were compared to those of another dihydropyridine, Bay w 9798, which has no calcium‐antagonistic properties in concentrations up to 10 μM, as verified by superfusion bioassay.

Both, nifedipine and Bay w 9798, in concentrations ranging from 0.01 to 1 μM, augmented the interleukin‐1β/tumour necrosis factor‐α (IL‐1β/TNF‐α)‐induced expression of the inducible isoform of nitric oxide synthase (iNOS) in rat aortic cultured smooth muscle cells (raSMC) 2–3 fold, as judged by RT–PCR and Western blot analyses.

In contrast, cytokine‐induced mRNA expression of monocyte chemoattractant protein 1 (MCP‐1) in these cells was down‐regulated by more than 60% in the presence of both dihydropyridines, as judged by RT–PCR and Northern blot analyses.

Nuclear run‐on assays and incubation with the transcription‐terminating drug actinomycin D revealed that both drugs acted at the level of mRNA synthesis rather than stability.

These findings suggest that 1,4‐dihydropyridines such as nifedipine affect the expression of both potentially pro‐arteriosclerotic (MCP‐1) and anti‐arteriosclerotic (iNOS) gene products in the vessel wall at the level of transcription, and that these effects are unrelated to their calcium channel‐blocking properties.

British Journal of Pharmacology (2000) 129, 1155–1162; doi:10.1038/sj.bjp.0703192

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Indication	Highest Phase	Country/Location	Organization	Date
Peripheral Vascular Diseases	Phase 2	US	-	-
Peripheral Vascular Diseases	Phase 2	DE	Bayer AG	-

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