Table 3.

Mixed mitochondrial effects of cardiovascular drugs.

Class of Drugs	Drug Name	Beneficial Effects	Experimental Model	Deleterious Effects	Experimental Model	References
	Antiarrhytmics
	Lidocaine	Alleviation of isoflurane-induced mitochondrial structure damage and the decline in mitochondrial membrane potential 40–100 μg/mL) Reversal of isoflurane-induced mitochondrial ETS dysfunction (40–100 μg/mL) Inhibition of isoflurane-induced apoptosis (40–100 μg/mL)	in vitro (H4 cells exposed to isoflurane)	Suppression of the mitochondrial ETS (0.1–10 mM) Decreased mitochondrial membrane potential (0.1–10 mM) Increased ROS production (0.1–10 mM) Inhibition of ATP synthesis (0.1–10 mM) Induction of mitochondrial structural changes and apoptosis (4–4000 µM)	in vitro (neuronal SH-SY5Y cells) in vitro (human neutrophils)	[152,153,154]
	Phenytoin	Decreased cerebral malondialdehyde as marker of oxidative stress Decreased monoamine oxidase A + B activity in an animal model of epilepsy	in vivo	Increased oxidative stress (200–600 µM) Depletion of glutathione (200–600 µM) Increased lipid peroxidation (200–600 µM) Inhibition of respiration (0.025–1 mM) Decreased ATP synthesis (0.025–1 mM) Decreased mitochondrial membrane potential (0.025–1 mM)	in vitro (rat hepatocytes) in vitro (murine hepatic microsomal system)	[155,156,157]
Class II (β-blockers)	Carvedilol	Antioxidant effects (10 µM) Inhibition of lipid peroxidation (1–50 µM) Mild uncoupling of mitochondrial oxidative phosphorylation (10–100 µM) Decrease in ROS production (10–20 µM) Prevention of calcium overload (10–20 µM) Inhibition of NADH dehydrogenase and prevention of oxidative damage (10–20 µM) Inhibition of mPTP (5–20 µM)	in vitro (swine ventricular membranes, rat brain homogenates, human LDL, bovine and human endothelial cells, rat heart mitochondria)	Induction of severe mitochondria damage—mitochondrial swelling, crista damage and formation of myelin figures inside the mitochondria (10 µM)	in vitro (rat C6 glioma cells)	[158,159,160,161]
	Nebivolol	Antioxidant activity (1–2 mg/kg, 8 weeks) Inhibition of NADPH oxidase activity (1–2 mg/kg, 8 weeks)	in vivo (streptozocin treated diabetic rats)	Inhibition of complex I and V (1 µM) Inhibition of respiration (1 µM) Depletion of ATP levels (10 µM) Induction of mitochondrial morphology changes (10 µM) Increased ROS production (10 µM)	in vitro (breast, colon and oral squamous carcinoma cells)	[162,163,164]
	Metoprolol	Increased mitochondrial respiratory control ratio (1 mg/kg -bolus infusion)	in vivo (rat model of ischemia/reperfusion injury)	No protective effect against adriamycin-induced mitochondrial DNA impairment (3 mg/kg/12 h, 12 days)	in vivo (rat model of adriamycin-induced cardiotoxicity)	[165,166,167,168]
	Atenolol	Decrease in membrane fatty acid unsaturation degree of mitochondria (0.1 g/L of atenolol drinking water solution) Reduction in mitochondrial protein oxidative, glycoxidative, and lipoxidative modification (0.1 g/L in drinking water) Reduction in oxidative damage in heart mitochondrial DNA (0.1 g/L in drinking water)	in vivo (rats)	Increased ROS production (2.5–20 μg/mL) Decrease in mitochondrial succinate dehydrogenase activity (2.5–20 μg/mL) Decreased mitochondrial membrane potential (2.5–20 μg/mL) Induction of mitochondrial swelling (2.5–20 μg/mL) Decreased ATP content (2.5–20 μg/mL)	in vitro (isolated rat heart mitochondria)	[119,169,170,171]
	Esmolol	Improvement of mitochondrial morphology (300 μg/kg/min, 48 h) Prevention of apoptosis by decreasing the Bax/Bcl-2 levels (1.75–3.5 mg/Kg/h)	in vivo (spontaneously hypertensive rats) in vivo (early sepsis rats with abdominal infection)	Increased ROS level (5–250 μM) Decreased mitochondrial membrane potential (5–250 μM)	in vitro (human lung fibroblast cells)	[172,173,174,175]
Others	Adenosine	Attenuation of the decline of complex I and mitochondrial NO synthase activities (0.03 μg/kg/min, 65 min) Reduction in mitochondrial phospholipid oxidation (0.03 μg/kg/min, 65 min)	ex vivo (experimental model of rabbit heart ischemia/reperfusion)	Induction of apoptosis (0.1–10 mM) Increased ROS production (0.1–10 mM) Reduction in Bcl-X(L) expression (3 mM) Disruption of mitochondrial membrane potential (3 mM)	in vitro (liver cancer cells) in vitro (HepG2 cells)	[176,177,178,179]
	Digitalis	Enhancement of the efficiency of mitochondrial electron transport and ATP synthesis (1–100 nM in vitro; 1 mg/kg, 5–8 days in vivo)	in vitro (rat cardiomyocytes) in vivo (mice)	Reduction in mitochondrial Ca2+ accumulation (1 µM) Reduction in the NADH/NAD+ redox potential (1 µM) Increased ROS production (1 µM) Decrease mitochondrial membrane potential (0.025–0.2 µM) Induction of mitochondrial related apoptosis (0.025–0.2 µM) Increase Bax/Bcl-2 proportion (50–200 nM) Depletion of ATP (0.03–100 µM)	in vitro (guinea pig ventricular myocytes) in vitro (human non-small cell lung cancer cells A549) in vitro (breast cancer cells) in vitro (HeLa cell line)	[180,181,182,183,184,185]
Angiotensin-converting enzyme inhibitors (ACEI)	Ramipril	Attenuation of lipid peroxidation (10 mg/kg/day, 28 days in vivo; 10 µM in vitro)	in vivo (rat model of rheumatoid arthritis) and in vitro (rat cardiomyocytes)	Inhibition of cardiac uncoupling protein-2 expression (50 µg/kg/day, 4 weeks)	in vivo (rat model of ischemia/reperfusion)	[186,187]
	Captopril	Attenuation of mitochondrial membrane potential dissipation (10 mg/kg, 7–8 days) Increase ATP production (10 mg/kg, 7–8 days) Restoration of mitochondrial oxygen consumption (5 mg/kg, 12 weeks) Antioxidant effect (0.08 mM)	in vivo (rat model of adriamycin toxicity) in vivo (rabbits with experimentally induces hypercholesterolemia) in vitro (rat liver mitochondria)	Decrease in respiration rates (5 mg/kg, 12 weeks) Inhibition of ATP synthase activity (0.1–0.5 mmol/L)	in vivo (rabbits with experimentally induces hypercholesterolemia) in vitro (rat heart mitochondria)	[188,189,190,191,192]
	Lisinopril	Attenuation of oxidative stress (40 mg/L in drinking water) Increase mitochondrial content (40 mg/L in drinking water)	in vivo (rat model of irradiation-induced kidney damage)	Reduction in mitochondrial respiration (50–10,000 ng/mL)	in vitro (Drosophila melanogaster strains)	[193,194]
Direct Oral Anticoagulants	Rivaroxaban	Reduction in ROS generation (300 nM in vitro; 12 mg/kg/day, 28 days in vivo) Antioxidant effects (5.6 mM)	in vitro (advanced glycation end products-exposed proximal tubular cells); in vivo (intermittent hypoxia exposed mice) in vitro (rat kidney mitochondria)	Decrease in mitochondrial succinate dehydrogenase activity (1.4–2.8 mM) Increase ROS production (1.4–2.8 mM) Induction of mitochondrial swelling (1.4–2.8 mM) Reduction in mitochondrial membrane potential (1.4–2.8 mM)	in vitro (rat kidney mitochondria)	[195,196,197]
	Diuretics
Epithelial sodium channel blockers	Amiloride	Attenuation of the mitochondrial membrane potential dissipation (50–200 μM) Inhibition of apoptosis (50–200 μM)	in vitro (rat articular chondrocytes)	Inhibition of mitochondrial NADH-quinone oxidoreductase (complex I) (5–100 µM) Inhibition of oxidative phosphorylation (10 µM) Increased mitochondrial fusion (10 µM)	in vitro (in bovine submitochondrial particles and in bacterial membranes) in vitro (clonal untransformed and cancer cells)	[198,199,200]
Statins		Enhancement of mitochondrial respiration (2.5–10 µM Simva) Increase in complex I and IV activity (2.5–10 µM Simva)	in vitro (peripheral blood mononuclear cells and platelets)	Reduction in coenzyme Q10 level (1–100 µM) Increase in ROS generation (25–700 µM) Inhibition of respiration (1–1000 µmol/L) Inhibition of respiratory chain complexes (1–1000 µmol/L) Uncoupling of oxidative phosphorylation (1–1000 µmol/L) Reduction in ATP production (1–1000 µmol/L) Induction of mitochondrial membrane depolarization (1–1000 µmol/L) Induction of mitochondrial apoptosis (1–1000 µmol/L) Induction of mitochondrial swelling (1–1000 µmol/L) Dysregulation of calcium metabolism (25–700 µM) Induction of fatty acid oxidation (Simva, 80 mg/day, 12 weeks)	in vitro (rat myoblasts, isolated rat skeletal muscle mitochondria, isolated endothelial mitochondria, rat hepatocytes, pancreas mitochondria, human platelets) in vivo	[201,202,203,204,205,206,207]
Direct vasodilators	Hydralazine	Antioxidant properties (10–30 mg/kg) Inhibition of apoptosis (10–30 mg/kg) Inhibition of mitochondrial fission (1 µM) Preservation of mitochondrial fusion (1 µM) Promotion of mitochondrial biogenesis (5–20 µM) Increase in ETS complexes activity (5–20 µM) Increase in ATP production (5–20 µM) Enhancement of mitochondrial membrane potential (5–20 µM) Increase in mtDNA/nDNA ratio (5–20 µM) Increase in mitochondrial mass (5–20 µM)	in vivo (rat model of ischemia/reperfusion) in vitro (isolated murine cardiomyocytes subjected to ischemia/reperfusion injury) in vitro (human neuroblastoma SH-SY5Y and mouse myoblast C2C12 cells)	Inhibition of respiration (10–100 µM) Induction of apoptosis (200–600 µM) Increase ROS production (200–600 µM) Reduction in mitochondrial membrane potential (200–600 µM)	in vitro (human neuroblastoma SH-SY5Y and mouse myoblast C2C12 cells) in vitro (leukemic T cells)	[208,209,210] [211,212]
Sodium-glucose cotransporter 2 (SGLT2) inhibitors	Dapagliflozin	Antioxidant properties (10 µM) Reduction in ROS production (0.1–10 μM) Alteration of Ca2+ dynamics (0.01–10 μM) Decrease in mitochondrial swelling (1 mg/kg) Reduction in mitochondrial fission (1 mg/kg/day, 28 days) Increase in mitochondrial fusion (1 mg/kg/day, 28 days) Normalization of respiratory control ratio (1 mg/kg/day, 20 days) Decrease lipid peroxidation (1 mg/kg/day, 20 days)	in vitro (rat liver mitochondria) in vitro (human proximal tubular cells) in vivo (rat model of ischemia/reperfusion injury) in vivo (metabolic syndrome rats subjected to ischemia/reperfusion) in vivo (mice model of streptozocin induced diabetes)	Inhibition of mitochondrial respiration (20–50 µM) Reduction in calcium retention capacity (20–50 µM)	in vitro (rat liver mitochondria)	[213,214,215,216,217]
	Canagliflozin	Improvement of mitochondrial biogenesis (60 mg/kg/day, 14 weeks) Improvement of fatty acid oxidation (60 mg/kg/day, 14 weeks)	in vivo (mice model of high-fat diet induced obesity)	Inhibition of the ETS complex I (10–50 µM) Inhibition of the ETS complex II (50 µM)	in vitro (human renal proximal tubule epithelial cell model system) in vitro (breast cancer cells)	[218,219] [220]