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Synergistic Effect of Amlodipine and Atorvastatin in Reversing LDL-Induced Endothelial Dysfunction

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Abstract

Purpose

Statins and certain calcium channel blockers may improve nitric oxide (NO) release and endothelial function through various mechanisms, but their combined effects are not well understood.

Methods

The separate versus combined effects of amlodipine (AML) and atorvastatin (AT) on NO and peroxynitrite (ONOO−) were measured in human umbilical vein endothelial cells (HUVEC) in the presence and absence of low-density lipoprotein (LDL) using electrochemical nanosensors.

Results

The combination of AML (5 μmol/l) and AT (3-6 μmol/l) directly stimulated NO release that was about twofold greater than the sum of their separate effects (p < 0.05). This synergistic activity is attributed to enhanced endothelial NO synthase (eNOS) function and decreased cytotoxic ONOO−. LDL (100 mg/dl) caused a dysfunction of HUVEC manifested by a 60% reduction in NO and an almost twofold increase in ONOO−. Treatment with AML/AT partially reversed the effects of LDL on endothelial function, including a 90% increase in NO and 50% reduction in ONOO−. Small-angle X-ray diffraction analysis indicates that AML and AT are lipophilic and share an overlapping molecular location in the cell membrane that could facilitate electron transfer for antioxidant mechanisms.

Conclusion

These findings indicate a synergistic effect of AML and AT on an increase in NO concentration, reduction of nitroxidative stress. Also, AML/AT partially restored the NO level of LDL-induced dysfunctional endothelium. Their combined effects may be enhanced by antioxidant properties related to their intermolecular actions in the cell membrane and an increase in the expression and coupling of endothelial nitric oxide synthase.

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Authors and Affiliations

  1. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    R. Preston Mason

  2. Elucida Research, Beverly, Massachusetts, USA

    R. Preston Mason, Robert F. Jacob, Charles A. Day & Yehudi S. Medlin

  3. Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA

    Ruslan Kubant, Gehan Heeba, Philipp Funovics & Tadeusz Malinski

  4. University Clinic of Orthopedic Surgery, Medical University of Vienna, Vienna, Austria

    Philipp Funovics

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  1. R. Preston Mason
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  2. Ruslan Kubant
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  4. Robert F. Jacob
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Correspondence to Tadeusz Malinski.

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Mason, R.P., Kubant, R., Heeba, G. et al. Synergistic Effect of Amlodipine and Atorvastatin in Reversing LDL-Induced Endothelial Dysfunction. Pharm Res 25, 1798–1806 (2008). https://doi.org/10.1007/s11095-007-9491-1

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