Research Paper

Pharmaceutical Research

, Volume 25, Issue 8, pp 1798-1806

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

  • R. Preston MasonAffiliated withDepartment of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolElucida Research
  • , Ruslan KubantAffiliated withDepartment of Chemistry and Biochemistry, Ohio University
  • , Gehan HeebaAffiliated withDepartment of Chemistry and Biochemistry, Ohio University
  • , Robert F. JacobAffiliated withElucida Research
  • , Charles A. DayAffiliated withElucida Research
  • , Yehudi S. MedlinAffiliated withElucida Research
  • , Philipp FunovicsAffiliated withDepartment of Chemistry and Biochemistry, Ohio UniversityUniversity Clinic of Orthopedic Surgery, Medical University of Vienna
  • , Tadeusz MalinskiAffiliated withDepartment of Chemistry and Biochemistry, Ohio University Email author 

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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.

Key Words

endothelium LDL nitric oxide oxidative stress