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Title: Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

Abstract

Statins induce acute vasorelaxation which may contribute to the overall benefits of statins in the treatment of cardiovascular disease. The mechanism underlying this relaxation is unknown. As statins have been shown to alter mitochondrial function, in this study we investigated the role of mitochondria in the relaxation to simvastatin. Relaxation of porcine coronary artery segments by statins was measured using isolated tissue baths. Mitochondrial activity was determined by measuring changes in rhodamine 123 fluorescence. Changes in intracellular calcium levels were determined in freshly isolated smooth muscle cells with Fluo-4 using standard epifluorescent imaging techniques. Simvastatin, but not pravastatin, produced a slow relaxation of the coronary artery, which was independent of the endothelium. The relaxation was attenuated by the mitochondrial complex I inhibitor rotenone (10 μM) and the complex III inhibitor myxothiazol (10 μM), or a combination of the two. The complex III inhibitor antimycin A (10 μM) produced a similar time-dependent relaxation of the porcine coronary artery, which was attenuated by rotenone. Changes in rhodamine 123 fluorescence showed that simvastatin (10 μM) depolarized the membrane potential of mitochondria in both isolated mitochondria and intact blood vessels. Simvastatin and antimycin A both inhibited calcium-induced contractions in isolated blood vessels and calciummore » influx in smooth muscle cells and this inhibition was prevented by rotenone. In conclusion, simvastatin produces an endothelium-independent relaxation of the porcine coronary artery which is dependent, in part, upon effects on the mitochondria. The effects on the mitochondria may lead to a reduction in calcium influx and hence relaxation of the blood vessel. - Highlights: • Simvastatin produces a relaxation of the porcine coronary artery. • This relaxation is inhibited by mitochondrial complex inhibitors. • Simvastatin alters mitochondrial membrane potential in intact blood vessels. • Simvastatin inhibits calcium influx in smooth muscle cells, prevented by a mitochondrial inhibitor. • Simvastatin-induced relaxations are dependent upon mitochondrial activity.« less

Authors:
; ;
Publication Date:
OSTI Identifier:
22689237
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 305; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBIOTICS; BLOOD; CALCIUM; CARBONYLS; CARDIOVASCULAR DISEASES; COBALT ARSENIDES; CORONARIES; CYANIDES; ENDOTHELIUM; FLUORESCENCE; INHIBITION; MEMBRANES; MITOCHONDRIA; MUSCLES; OXIDOREDUCTASES; RELAXATION; RHODAMINES; TIME DEPENDENCE; VASODILATION

Citation Formats

Almukhtar, H., Garle, M. J., Smith, P. A., and Roberts, R.E., E-mail: richard.roberts@nottingham.ac.uk. Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria. United States: N. p., 2016. Web. doi:10.1016/J.TAAP.2016.06.024.
Almukhtar, H., Garle, M. J., Smith, P. A., & Roberts, R.E., E-mail: richard.roberts@nottingham.ac.uk. Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria. United States. https://doi.org/10.1016/J.TAAP.2016.06.024
Almukhtar, H., Garle, M. J., Smith, P. A., and Roberts, R.E., E-mail: richard.roberts@nottingham.ac.uk. 2016. "Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria". United States. https://doi.org/10.1016/J.TAAP.2016.06.024.
@article{osti_22689237,
title = {Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria},
author = {Almukhtar, H. and Garle, M. J. and Smith, P. A. and Roberts, R.E., E-mail: richard.roberts@nottingham.ac.uk},
abstractNote = {Statins induce acute vasorelaxation which may contribute to the overall benefits of statins in the treatment of cardiovascular disease. The mechanism underlying this relaxation is unknown. As statins have been shown to alter mitochondrial function, in this study we investigated the role of mitochondria in the relaxation to simvastatin. Relaxation of porcine coronary artery segments by statins was measured using isolated tissue baths. Mitochondrial activity was determined by measuring changes in rhodamine 123 fluorescence. Changes in intracellular calcium levels were determined in freshly isolated smooth muscle cells with Fluo-4 using standard epifluorescent imaging techniques. Simvastatin, but not pravastatin, produced a slow relaxation of the coronary artery, which was independent of the endothelium. The relaxation was attenuated by the mitochondrial complex I inhibitor rotenone (10 μM) and the complex III inhibitor myxothiazol (10 μM), or a combination of the two. The complex III inhibitor antimycin A (10 μM) produced a similar time-dependent relaxation of the porcine coronary artery, which was attenuated by rotenone. Changes in rhodamine 123 fluorescence showed that simvastatin (10 μM) depolarized the membrane potential of mitochondria in both isolated mitochondria and intact blood vessels. Simvastatin and antimycin A both inhibited calcium-induced contractions in isolated blood vessels and calcium influx in smooth muscle cells and this inhibition was prevented by rotenone. In conclusion, simvastatin produces an endothelium-independent relaxation of the porcine coronary artery which is dependent, in part, upon effects on the mitochondria. The effects on the mitochondria may lead to a reduction in calcium influx and hence relaxation of the blood vessel. - Highlights: • Simvastatin produces a relaxation of the porcine coronary artery. • This relaxation is inhibited by mitochondrial complex inhibitors. • Simvastatin alters mitochondrial membrane potential in intact blood vessels. • Simvastatin inhibits calcium influx in smooth muscle cells, prevented by a mitochondrial inhibitor. • Simvastatin-induced relaxations are dependent upon mitochondrial activity.},
doi = {10.1016/J.TAAP.2016.06.024},
url = {https://www.osti.gov/biblio/22689237}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 305,
place = {United States},
year = {Mon Aug 15 00:00:00 EDT 2016},
month = {Mon Aug 15 00:00:00 EDT 2016}
}