Effects of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts

Abstract

1 Effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Qi0, and on mitochrondrial respiration were examined in dogs.2 Either vehicle (control), pravastatin (4 mg kg-'day-), or simvastatin (2 mg kg-'day-') was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Qio was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates. 3 Simvastatin significantly decreased the myocardial level of coenzyme Qio, but pravastatin did not. 4 Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin-treated groups. 5Only in the simvastatin-treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate. 6 The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Qio level.

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

“…Simvastatin is widely used in clinical management, and if it is found to prevent atrial tachycardia remodeling in humans, it might prove a useful tool to test the value of atrial remodeling prevention in AF therapy. The doses of simvastatin that we studied (2 · kg Ϫ1 · d Ϫ1 ) are equal to those used in some experimental dog studies 36 and smaller than in others 37 but are somewhat higher than those in common clinical use (0.3 to 1 mg/kg). It remains to be determined whether clinically used doses of simvastatin are able to prevent atrial tachycardia remodeling in humans.…”

Atorvastatin-Induced Changes in Plasma Coenzyme Q10 and Brain Natriuretic Peptide in Patients With Coronary Artery Disease

“…Previous animal and human studies 12,21) reported detrimental influences of statins on mitochondrial respiration. In the study of Silver, et al, 28) patients with hypercholesterolemia but without LV systolic dysfunction had a worsening of LV diastolic function after 3 to 6 months of ATO therapy, but CoQ10 supplementation improved the diastolic dysfunction.…”

“…11) On the other hand, lovastatin decreased myocardial CoQ10 levels in rats and supplementation with CoQ10 restored them. 20) Satoh, et al 21) suggested that a lipid-soluble statin might enter myocardial cells and prevent ubiquinone synthesis through the inhibition of HMG-CoA reductase, while a water-soluble statin would not decrease the myocardial CoQ10 level. Therefore, these differences between water-soluble and lipid-soluble statins may affect the tissue levels of CoQ10.…”

Molecular mechanisms of toxicity of simvastatin, widely used cholesterol-lowering drug. A review

“…Simvastatin administered to dogs for 3 weeks significantly decreases the myocardial level of CoQ and causes worsening of the myocardial mitochondrial respiration [64]. When simvastatin is administered orally to mice, the levels of CoQ in liver and heart decreases significantly while the levels of thiobarbituric acid reactive substances in liver and heart mitochondria increases significantly [58].…”

“…Human skeletal muscle Mitochondrial DNA fragmentation [62] Rat skeletal muscle Changes in mitochondrial morphology [35] Rabbit skeletal muscle Mitochondrial swelling and a decrease in CoQ [34] Dog myocardium Decrease in CoQ and mitochondrial respiration [64] Rat lens Decrease in CoQ [38] Mouse liver and heart mitochondria Decrease in CoQ, increase in lipid peroxidation products [58] inhibitor of calcineurin and mitochondrial permeability transition (MPT). At 60 µM, simvastatin induced the necrosis preceded by a threefold increase in cytosolic free Ca 2+ concentration and a significant decrease in both respiration rate and mitochondrial membrane potential.…”