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

• Published in: Pharmaceutical research Vol. 25; no. 8; pp. 1798 - 1806
• Main Authors: Mason, R. Preston, Kubant, Ruslan, Heeba, Gehan, Jacob, Robert F., Day, Charles A., Medlin, Yehudi S., Funovics, Philipp, Malinski, Tadeusz
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.08.2008; Springer; Springer Nature B.V
• Subjects: Amlodipine - pharmacology; Atorvastatin Calcium; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blotting, Western; Calcium Channel Blockers - pharmacology; Cells, Cultured; Cellular biology; Drug Synergism; Endothelium, Vascular - drug effects; General pharmacology; Heptanoic Acids - pharmacology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lipid Bilayers; Lipoproteins, LDL - antagonists & inhibitors; Lipoproteins, LDL - toxicity; Low density lipoprotein; Medical Law; Medical sciences; Membrane Lipids - chemistry; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - biosynthesis; Peroxynitrous Acid - pharmacology; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Pyrroles - pharmacology; Research Paper; Statins; Vascular Diseases - chemically induced; Vascular Diseases - drug therapy; X-Ray Diffraction; endothelium; nitric oxide; LDL; oxidative stress; Antianginal agent; Oxidative stress; Pharmaceutical technology; Enzyme; Calcium antagonist; Enzyme inhibitor; Statin derivative; Hypocholesterolemic agent; Endothelium; HMG-CoA reductase inhibitor; Nitric oxide; Amlodipine; Atorvastatin; Endothelial dysfunction; Hydroxymethylglutaryl-CoA reductase; Antihypertensive agent; Reversibility; Dihydropyridine derivatives; Oxidoreductases; Antilipemic agent
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-007-9491-1

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.