Table 1.
Beneficial mitochondrial effects of cardiovascular drugs.
| Class of Drugs | Drug Name | Mitochondrial Effects | Experimental Model | References |
|---|---|---|---|---|
| Antiarrhytmics | ||||
| Class II (β-blockers) |
Timolol | Prevention of oxidative damage (25–5000 µM) Prevention of lipid peroxidation (5 mg/kg body weight, 9 months) |
in vitro in vivo (female rat model of aging-related altered left ventricular function) |
[28,29,30,31] |
| Class III (K-channel blockers) |
Ibutilide | Attenuation of oxidative stress (10−8 to 10−3 mol/L) Inhibition of mitochondrial-related apoptosis Increase in glutathione peroxidase and superoxide dismutase levels (10−8 to 10−3 mol/L) |
in vitro (rat cardiomyocytes) | [32] |
| Sotalol | No mitochondrial dysfunction (15–240 µM) | in vitro (human platelets) | [33] | |
| Dofetilide | Correction of the calcium handling (2 mg/kg, 3 days; 10−6–10−8 mol/L) Correction of NADPH oxidase (2 mg/kg, 3 days; 10−6–10−8 mol/L) |
in vivo (heart failure rat model) in vitro (primary neonatal cardiomyocytes) |
[34] | |
| Class IV (Ca-channel blockers) |
Verapamil | Inhibition of lipid peroxidation (7 mg/kg) Antioxidant enzyme activity (10 mg/kg twice) Reduction in apoptosis (10 mg/kg twice) Reduction in ROS formation and cytochrome c release (10 mg/kg twice) Increase the ATP concentration (10 mg/kg twice) Reduction in mitochondrial swelling (10 mg/kg twice) Inhibition of mitochondrial membrane potential decrease (10 mg/kg twice) |
in vivo (streptozotocin-induced diabetic rats) in vivo (rat model of forebrain ischemia/reperfusion) |
[35,36] |
| Diltiazem | Protection of mitochondrial integrity (0.1–0.5 µmol/L) Conservation of high-energy phosphate levels (200 µg/kg bolus + 15 µg/kg/min continuous iv infusion) Prevention of mitochondrial swelling (7.5 µM) Prevention of mitochondrial Ca2+ increase (7.5 µM) Reduction in lipid peroxidation (5 × 10−7M) Decrease apoptosis (10 µmol/L) |
ex vivo (drug administered during reperfusion in a rabbit model of heart ischemia/reperfusion) in vivo (rabbit model of myocardium ischemia/reperfusion) ex vivo (drug added before ischemia in a rat model of heart ischemia/reperfusion) ex vivo (reperfused isolated rabbit hearts) in vitro (rat hepatocytes) |
[37,38,39,40,41] | |
| Angiotensin-converting enzyme inhibitors (ACEI) | Zofenopril | Prevention of mitochondrial calcium overload (10−9–10−4 M) Maintenance of oxidative phosphorylation (10−9–10−4 M) Maintenance of ATP production (10−9–10−4 M) Preservation of membrane integrity (10−9–10−4 M) Decrease oxidative stress (10−9–10−4 M) |
ex vivo (rabbit model of myocardium ischemia/reperfusion) | [42] |
| Perindopril | Decreased ROS synthesis (2 mg/kg/day, 6 weeks) Increased antioxidant enzymes (2 mg/kg/day, 6 weeks) Increased number of mitochondria (2 mg/kg/day, 6 weeks) Alleviation of mitochondrial ETS dysfunction (2 mg/kg/day, 6 weeks) Increase ATP production (2 mg/kg/day, 6 weeks) Reduction in apoptosis (2 mg/kg/day, 6 weeks) Increased calcium retention capacity (0.2 mg/kg) |
in vivo (rat model of isoprotenerol-induced cardiomyopathy) in vivo (drug administered prior to ischemia in a pig model of heart ischemia/reperfusion) |
[43,44] | |
| Trandolapril | Increase in ETS complexes I, II and IV activities (4–6 mg/kg/day, 12 days) Attenuation of oxidative stress (4–6 mg/kg/day, 12 days) Reduction in lipid peroxidation (4–6 mg/kg/day, 12 days) Improvement of mitochondrial oxygen consumption rates (3 mg/kg/day, 6 weeks) Increase in ATP production (3 mg/kg/day, 6 weeks) |
in vivo (in a rat model of 3-nitropropionic acid induced brain lesions) in vivo (rat model of failing heart following acute myocardial infarction) |
[45,46,47] |
|
| Enalapril | Enhance antioxidant defenses (20 mg/L in drinking water, 11 weeks) Decreased ROS production (10 mg/kg/day, 14 days) Increased mitochondrial mass/biogenesis (20 mg/kg/day, 3 months) Promotion of mitochondrial fusion and autophagy (20 mg/kg/day, 3 months) Reduction in lipid peroxidation (10 mg/kg/day, 12 weeks) Improvement of mitochondrial respiratory efficiency (10 mg/kg/day, 10 weeks) |
in vivo (mouse tissues) in vivo (rat kidney mitochondria) in vivo (aged rat hearts) in vivo (rat model of heart failure) in vivo (rat model of doxorubicin-induced cardiomyopathy) |
[48,49,50,51,52] | |
| Angiotensin receptor blockers (ARBs) | Valsartan | Improvement of mitochondrial biogenesis and mitophagy (320 mg/day, 4 weeks) Increase mitochondrial respiration (15 mg/kg/day, 4 months) Reduction in mitochondrial oxidative stress (30 mg/kg/day in drinking water, 3 weeks) Increase in mitochondrial β-oxidation (30 mg/kg/day in drinking water, 3 weeks) |
in vivo (pig model with renovascular hypertension) in vivo (rats with type 2 diabetes) in vivo (rats with elevated levels of angiotensin II) |
[53,54,55] |
| Losartan | Reduction in oxidative stress (40 mg/kg/day, 6 months) Increased mitochondrial membrane potential (40 mg/kg/day, 6 months) Amelioration of mtDNA content decrease (30 mg/kg/day, 16.5 months) Improvement of mitochondrial biogenesis (100 mg/L in drinking water, 30 days) |
in vivo (spontaneously hypertensive rats) in vivo (aged rats) in vivo (obese mice) |
[56,57,58] | |
| Candesartan | Decreased ROS production (10 μmol/L) Regulation of mitochondrial dynamics (10 μmol/L) Improvement of mitochondrial structure and dynamics (2 mg/kg/day, 8 weeks) Increased mitochondrial membrane potential (2 mg/kg/day, 8 weeks) Alleviation of mitochondrial ETS dysfunction (Complex I, II, III, and IV) (0.1–0.3 mg/kg, 7 days) |
in vitro (vascular smooth muscle cells) in vivo (spontaneously hypertensive rats) in vivo (rat model of cerebral ischemia) |
[59,60,61] | |
| Irbesartan | Inhibition of mitochondrial apoptosis (50 mg/kg/day) Increase ATP production (10 nM) Increased mitochondrial membrane potential (10 nM) Decreased ROS production (10 nM) |
in vivo (rat model of sleep apnea) in vitro (human and mouse model of non-alcoholic fatty liver disease) |
[62,63] | |
| Telmisartan | Upregulation of mitochondria-specific genes expression (3–10 mg/kg) Increased mitochondrial membrane potential Decreased oxidative stress (5 mg/kg/day, 12 weeks) Modulation of mitochondrial Ca2+ homeostasis (5 mg/kg/day, 12 weeks) Enhancement of ATP synthesis (1–10 µM) Increase in mitochondrial complex II activity (1–10 µM) Reduction in apoptosis (1–10 µM) |
in vivo (mouse model of Parkinsonism) in vitro (renal glomerular endothelial cells exposed to high glucose) in vivo (hypertensive rats) in vitro (human vascular smooth muscle cells) |
[64,65,66,67] |
|
| Olmesartan | Increase in mitochondrial ETS activities (complex I, II) (10 mg/kg/day, 6 weeks) Reduction in oxidative damage (3 mg/kg/day in drinking water, 8 weeks) Improvement of ADP-dependent mitochondrial respiration (3 mg/kg/day in drinking water, 8 weeks) |
in vivo (obese insulin resistant rats exposed to an acute glucose load) in vivo (mice model of high-fat diet-induced diabetes) |
[68,69] | |
| Azilsartan | Decreased ROS production (0.1–10 µM) Inhibition of lipid peroxidation (0.1–10 µM) Increased mitochondrial membrane potential (0.1–10 µM) Preservation of ATP production (0.1–10 µM) Reduction in mitochondrial swelling (0.1–10 µM) Alleviation of ETS complexes I, II and IV dysfunction Increased mitochondrial respiration (2–4 mg/kg) Inhibition of apoptosis (2–4 mg/kg) Increased glutathione level (2–4 mg/kg) |
in vitro (murine brain endothelial cells) in vivo (rat model of cerebral ischemia) |
[70,71] |
|
| Angiotensin receptor neprilysin inhibitor (ARNi) | Sacubitril/Valsartan | Attenuation of oxidative stress (68 mg/kg/day, 10 weeks) Improvement of mitochondrial state-3 respiration (100 mg/day, 3 months) Increased mitochondrial membrane potential (100 mg/day, 3 months) Prevention of mitochondrial permeability transition pore opening (100 mg/day, 3 months) Increased ATP production (100 mg/day, 3 months) Normalization of complex-I and IV activities (100 mg/day, 3 months) Inhibition of apoptosis (100 mg/day, 3 months) |
in vivo (rat model of pressure overloaded hearts) in vivo (dogs with experimental cardiorenal syndrome) |
[72,73] |
| Calcium channel blockers-dihydropyridines | Amlodipine | Increased oxygen consumption in state 3 (0.4 mg/kg) Increased calcium retention capacity (0.4 mg/kg) Reduction in ROS production (0.4 mg/kg) Decrease in mitochondrial swelling (0.4 mg/kg) Antioxidant properties (5 mg/kg/day, 8 weeks) Increased glutathione peroxidase, catalase and superoxide dismutase activity (1 mg/kg, 7 days) Reduction in lipid peroxidation (1 mg/kg, 7 days) Inhibition of apoptosis (1 mg/kg, 7 days) Enhancement of mitochondrial biogenesis (0.1–1000 μM) |
ex vivo (pig ischemia/reperfusion model) in vivo (cholesterol-induced rabbit model of atherosclerosis and a liver and a heart rat model of ischemia/reperfusion injury) in vitro (neural stem cells exposed to oxygen glucose deprivation) |
[44,74,75,76,77,78] |
| Antithrombotic agents |
Ticagrelor | Increased mitochondrial membrane potential (1 µM) Decreased ROS production (1 µM) Preservation of ATP synthesis (1 µM) Restoration of mitochondria ultrastructural changes (swelling and loss of crista) (1 µM) |
in vitro (insulin-resistant H9 c2 cells) | [79,80] |
| Oral anticoagulants | ||||
| Direct oral anticoagulants | Apixaban | Antioxidant properties (60 ng/mL) Reduction in ROS production (60 ng/mL) |
in vitro (model of endothelial dysfunction in uremia) |
[81] |
| Edoxaban | Increase mitochondrial oxygen consumption (1 μmol/L) Improve mitochondrial ATP generation consumption (1 μmol/L) |
in vitro (human alveolar epithelial cells) |
[82] | |
| Diuretics | ||||
| Loop diuretics | Bumetanide | Attenuation of mitochondrial Ca2+ overload (5 μM) Attenuation of mitochondrial membrane potential dissipation (5 μM) Decreased cytochrome c release (5 μM) |
in vitro (astrocytes following ischemia) | [83,84] |
| Antagonists of aldosterone | Spironolactone | Improvement of mitochondrial membrane potential (0.01–1 µM) Increase in ATP synthesis (0.01–1 µM) Inhibition of ROS production (0.01–1 µM) Inhibition of apoptosis (1–10 µM) |
in vitro (methylglyoxal exposed osteoblastic cells) | [85,86] |
| Eplerenone | Increased number of cardiac mitochondria (100 mg/kg/day, 6 weeks) Increase in mitochondrial DNA copy number (100 mg/kg/day, 6 weeks) |
in vivo (aldosterone-infused mice) | [87] | |
| Sodium-glucose cotransporter 2 (SGLT2) inhibitors | Empagliflozin | Improvement of mitochondrial biogenesis (10–30 mg/kg/day, 8 weeks) Increased state 3 respiratory rate (10–30 mg/kg/day, 8 weeks) Increased mitochondrial membrane potential (10–30 mg/kg/day, 8 weeks) Suppression of ROS generation (10 mg/kg/day, 2 weeks) Reduction in mitochondrial DNA damage (30 mg/kg/day, 10 weeks) Reduction in oxidative stress (30 mg/kg/day, 10 weeks) Restoration of fatty acid oxidation (30 mg/kg/day, 10 weeks) Enhancement of mitochondrial fusion (3.8 mg/kg/day, 8 weeks) |
in vivo (rat model of high-fat diet/streptozocin-induced diabetes) in vivo (rat diabetic hearts after myocardial infarction) in vivo (rats with left ventricular dysfunction after myocardial infarction) |
[88,89,90,91,92,93] |
| Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) |
Liraglutide | Decreased ROS production (50–500 nM) Increased mitophagy (50–500 nM) Alleviation of mitochondrial membrane potential decrease (1–20 nM) Inhibition of mitochondrial permeability transition pore opening (1–20 nM) Inhibition of apoptosis (1–20 nM) Attenuation of Ca2+ abnormalities (0.3 mg/kg, 4 weeks) Normalization of mitochondrial dynamics (0.15 mg/kg) |
in vitro (HepG2 cell model of non-alcoholic steatohepatitis) in vitro (human renal mesangial cells exposed to hyperglycemia) in vivo (rat model of high-carbohydrate induced metabolic syndrome) in vivo (acute mouse model of Parkinson’s disease) |
[94,95,96,97,98] |
| Exenatide | Decreased oxidative stress (0.05–0.6 μM) Increased ATP production (0.05–0.6 μM) Increased mitochondrial ATPase activity (0.05–0.6 μM) Increased mitochondrial membrane potential (0.05–0.6 μM) Decreased mitochondrial calcium overload (0.05–0.6 μM) Inhibition of mitochondrial permeability transition pore opening (0.05–0.6 μM) Improvement of morphological and structural changes of mitochondria (10 mg/kg or 0.3 nM) |
in vitro (H9c2 cardiomyocytes subjected to hypoxia/reoxygenation) in vivo (rat model of ischemia/reperfusion injury) and ex vivo (Langendorff model) |
[99,100] | |
| Dulaglutide | Increased mitochondrial membrane potential (50–100 nM) Decreased ROS generation (50–100 nM) Increased glutathione level (50–100 nM) |
in vitro (human fibroblast-like synoviocytes exposed to TNF-α) | [101] | |
| Semaglutide | Decreased ROS production (1–5 mmol/L) Improvement of autophagy (1–5 mmol/L) Decreased lipid peroxidation (25 nmol/kg, 30 days) |
in vitro (lipopolysaccharides treated H9c2 cardiomyocytes) in vivo (aged mice) |
[102,103] | |
| Lixisenatide | Promotion of mitochondrial biogenesis (5–20 nM) Increased mitochondrial respiration (5–20 nM) Enhancement of ATP generation (5–20 nM) Inhibition of oxidative stress (10–20 nM) Increased mitochondrial membrane potential (10–20 nM) |
in vitro (human umbilical vein endothelial cells) in vitro (human rheumatoid arthritis fibroblast-like synoviocytes) |
[104,105] | |