TABLE 3.
List of ligands known to activate cardiac specific T2Rs and their classification, number of T2Rs activated [bold indicates the receptor corresponding to the lowest threshold (TC) or effective concentration (EC50) in vitro concentration], reported effects in the cardiovascular system and corresponding dose/serum (* = based on 5.5 L of blood in human body, or without First Pass Effect of liver).
| Classification | Activates T2R (Jaggupilli et al., 2016) | In vitro (μM) - TC/EC50 Jaggupilli et al. (2016) | Reported effects on cardiovascular system | Reported doses | Reported or equivalent serum (μM) | |
| Bitter compounds in food | ||||||
| Absinthin | Sesquiterpene lactone | 10, 14, 30, 46 | 0.4 ± 0.06 (EC50) | – | – | – |
| Acesulfame K | Artificial sweetener | 31, 43 | 2500 ± 10 (EC50) | – | – | – |
| Apigenin | Flavonoid | 14, 39 | 20.5 (EC50) | – | – | – |
| Amarogentin | Secoiridoid glycoside | 30, 39, 43, 46, 50 | 65 ± 16 (EC50) | – | – | – |
| Andrographolide | Diterpenoid lactone | 30, 46, 50 | 13 ± 2.17 (EC50) | Shortened AP duration and reduced maximum upstroke (rabbits) (Zeng et al., 2017) | – | – |
| Aristolochic acid | Carcinogen | 14, 31, 43 | 0.081 ± 0.0008 (EC50) | Valvular heart disease - aortic sufficiency (Vanherweghem, 1997) | – | – |
| Caffeine | Stimulant | 10, 14, 43, 46 | 300 (TC) | Tachycardia, arrhythmia (Cappelletti et al., 2018) | 80–100 mg/L | >400 |
| Datiscetin | Flavonoid | 14, 39 | 10 (EC50) | – | – | – |
| (-)-Epicatechin | Antioxidant | 4, 5, 39 | 417.7 (EC50) | Promotes vasodilation (increase NO and decrease endothelin-1) (Schroeter et al., 2006; Loke et al., 2008; Mannaerts et al., 2017) | – | – |
| (-)-Epicatechin gallate (Ecg) | Flavonoid | 14, 39 | 70 (EC50) | – | – | – |
| (-)-Epigallocatechin gallate (EGCg) | Flavonoid | 14, 39 | 34 (EC50) | Reduction of diastolic BP (Brown et al., 2009) | 800 mg | ∼300 (without First Pass Effect)* |
| Falcarindiol | Antitumorigenic | 14 | 100 (TC) | – | – | – |
| Genistein | Phytoestrogen | 14, 39 | 28.9 (EC50) | – | – | – |
| Histidine | α-Amino acid | 39 | 430 (TC) | Arrhythmia prevention, inotropic support (Careaga et al., 2001; Teloh et al., 2016) | 198 mM | 8000–21000* |
| Humulone isomers | Alpha acid | 14 | 0.01 (TC) | Inhibit VEGF mediated angiogenesis and endothelial proliferation (mouse) (Shimamura et al., 2001) | – | 100 |
| Naringenin | Flavonoid | 14, 39 | 32.9 (EC50) | – | – | – |
| Procyanidin | Flavonoid | 5 | 35.6 ± 0.7 (EC50) | Improved hemodynamic parameters and collagen content (rats) (Martin-Fernandez et al., 2014) | 6500 mg (65 kg human, 100 mg/kg) | ∼2000 (without First Pass Effect)* |
| Quercetin | Flavonoid | 14 | 1 (TC) | Reduction in BP (Serban et al., 2016) | >500 mg | ∼300 (without First Pass Effect)* |
| Sodium benzoate | Preservative | 14, 16 | 300 (TC) | Caffeine alkaloid - combined with caffeine (Yucel et al., 1999) | – | – |
| Sinigrin | Glucosinolate | 16 | 100 (TC) | – | – | – |
| Thiamine | Vitamin B1 | 39 | 1000 (TC) | Deficiency results in wet beriberi (Lei et al., 2018) | – | – |
| Thujone, (-)-α | Stimulant | 10, 14 | 15 (EC50) | Arrhythmia, hypotension, vasodilation (rats) (Pinto-Scognamiglio, 1968) | 12480 mg (65 kg human, 192 mg/kg) | 15000 (without First Pass Effect)* |
| Chemicals/drugs | ||||||
| Allylthiourea | Nitrification inhibitor | 50 | 720 ± 150 (EC50) | – | – | – |
| Atropine | Muscarinic antagonist | 10, 46 | 100 (TC) | Tachycardia, arrhythmogenic (mice) (Perera et al., 2017) | – | – |
| Azathioprine | Immuno- suppressant | 4, 10, 14, 46 | 100 (TC) | Atrial fibrillation, hypotension, tachycardia, cardiogenic shock (Dodd et al., 1985; Brown et al., 1997) | 50 mg/day (2 weeks before hospital admission) | 32 (without First Pass Effect)* |
| Azithromycin | Antibiotic | 4 | 74.45 ± 12.3(EC50) | Ventricular tachycardia, prolongation of QT interval, torsades de pointes (Russo et al., 2006; Trifiro et al., 2017) | 500 mg/day i.v. | ∼115* |
| 4,4-Bipyridine | Bipyridine | 10, 14, 16 | 3680 ± 60 (EC50) | Other bipyridines used in heart disease and cardiac arrhythmias | – | – |
| Benzamide | Benzamides | 14 | 300 (TC) | Substituted benzamides linked to hypotension, prolongation of QT interval, ventricular arrhythmias | – | – |
| Carisoprodol | Muscle relaxer | 14 | 100 (TC) | Tachycardia, hypotension, heart palpitations (Rohatgi et al., 2005; Vo et al., 2017) | 71 mg/L | >250 |
| Chloroquine | Antimalarial | 3, 10, 39 | 172 ± 29 (EC50) | Cardiomyopathy, hypertrophy, ventricular arrhythmias: ST-segment depression, T wave inversion and QT interval prolongation, relaxation (Edwards et al., 1978; Stas et al., 2008; Tonnesmann et al., 2013) | 300 mg | >900 (without First Pass Effect)* |
| Chlorpheniramine | Antihistamine | 4, 10, 14, 39, 46 | 10 (TC) | QT interval prolongation, torsades de pointes tachycardia (Nia et al., 2010) | 2.5 mg (2.5 mg, two capsules three time a day) | ∼10 (without First Pass Effect)* |
| Chloramphenicol | Antibiotic | 10, 39, 41, 43, 46 | 10 (TC) | Gray Baby Syndrome - hypotension, arrhythmias; cardiovascular collapse (Sutherland, 1959; Biancaniello et al., 1981; Suarez and Ow, 1992) | 313 mg/L | >950 |
| Clonixin | NSAID | 14 | 2 (TC) | Cardiodepression and hypotension (rats) (Bustamante et al., 1989; Morales et al., 1995) | 7800 mg (65 kg human, 120 mg/kg - lethal dose i.v. rats) | >5000 (without First Pass Effect)* |
| Chlorhexidine | Antiseptic | 14 | 0.1 (TC) | Hemodynamic instability and vasodilatory shock (Guleri et al., 2012; Zhou et al., 2019) | Chlorhexidine-coated central venous catheter | – |
| Colchicine | Antigout | 4, 39, 46 | 1025 ± 121 (EC50) | Decreased rates of atrial fibrillation, pericarditis and atherosclerotic vascular disease; cardiac arrhythmias and cardiovascular collapse (Macleod and Phillips, 1947; Papageorgiou et al., 2017; Thompson, 2019) | 1 mg/day | 0.45 (without First Pass Effect)* |
| Cycloheximide | Eukaryote protein synthesis inhibitor | 10 | 100 (TC) | – | – | – |
| Cromolyn | Mast cell stabilizer | 20, 43 | 42 ± 25 (EC50) | Attenuates adverse LV remodeling and dysfunction in myocarditis, restored cardiac contractile dysfunction (rats) (Santone et al., 2008; Mina et al., 2013) | 1625 mg (65 kg human, 25 mg/kg i.p. rats) | 630 (without First Pass Effect)* |
| Dapsone | Antibiotic | 4, 10 | 100 (TC) | Myocardial injury, shock, ventricular dysrhythmia, cardiac arrest. Hypertension (Kang et al., 2016) (Lau, 1995; Zhu et al., 2009) | 300 mg–3 g | 219–2190 (without First Pass Effect)* |
| Denatonium benzoate | Deterring agent | 4, 10, 13, 30, 39, 43, 46 | 0.27 ± 0.06 (EC50) | Vasodilation (rats) (Lund et al., 2013) | 1 μM i.v. in rats | – |
| Dextromethorphan | Sedative | 10 | 10 (TC) | QT interval prolongation, torsades de pointes tachycardia, hypertension (Kaplan et al., 2011; Wu et al., 2012; Upadhyaya et al., 2014; Chew et al., 2017) | 1920 mg (27 mg/kg) | >1000 (without First Pass Effect)* |
| Diphenhydramine | Antihistamine | 14 | 30 (TC) | QT interval prolongation, ventricular tachycardia, hemodynamic collapse, cardiac arrest, junctional rhythm, complete right bundle branch block, hypotension (Yu et al., 2016; Abernathy et al., 2017; Labarinas et al., 2018; Nishino et al., 2018) | 18.7 mg/L | 73 |
| Diphenidol | Antiemetic | 4, 10, 13, 14, 16, 20, 30, 31, 39, 43, 46 | 3 (TC) | Contraction band necrosis (post mortem), hypotension, arrhythmia, including QT interval prolongation, T wave change, U wave appearance, AV block, bundle branch block, ventricular premature contraction, ventricular tachycardia and ventricular fibrillation (Wasserman et al., 1975; Yang and Deng, 1998; Zhang et al., 2015) | 45 mg/L | 145 |
| Erythromycin | Antibiotic | 10 | 300 (TC) | QT interval prolongation, torsades de pointes tachycardia, 68% increased of hospital-acquired cardiac events (arrhythmia, heart failure, myocardial ischemia) (Giudicessi et al., 2018; Postma et al., 2019) | 1300 mg (65 kg human, 15–20 mg/kg i.v. every 6 h) | >300* |
| Ethylhydrocupreine | Antibiotic | 14 | 10 (TC) | – | – | – |
| Famotidine | Antacid | 10, 31 | 300 (TC) | Cardiac arrest, third degree heart block, decreased stroke volume and cardiac output (Kirch et al., 1989; Schoenwald et al., 1999; Lee et al., 2004) | 2x 20 mg i.v. dose | >20* |
| Flufenamic acid | NSAID | 14 | 0.137 ± 0.017 (EC50) | Hypertension and congestive heart failure (Miyamori et al., 1985) | 600 mg | >350 (without First Pass Effect)* |
| Haloperidol | Antipsychotic | 10 | 30 (TC) | Prolongation of QT interval, torsades de pointes, sudden cardiac death (Meyer-Massetti et al., 2010; Fernandes et al., 2018; Vesely et al., 2019) | 2–1540 mg I.v. dose (cumulative) | 0.9–740* |
| Hydrocortisone | Medication form of cortisol | 46 | 30 (TC) | |||
| Levofloxacin | Antibiotic | 4, 14, 20 | 74.69 ± 20.5(EC50) | Ventricular tachycardia, prolongation of QT interval, torsades de pointes (Basyigit et al., 2005; Lu et al., 2015; Okeahialam, 2015) | 500 mg/day i.v. | ∼250* |
| Ofloxacin | Antibiotic | 9 | 200 (EC50) | – | – | – |
| Orphenadrine | Anticholinergic/antihistamine | 46 | 30 (TC) | Prolongation of QT interval, torsades de pointes, bradycardia, asystole (Malizia et al., 1980; Danze and Langdorf, 1991; Luzza et al., 2006) | 16.2 mg/L | >60 |
| Methoxsalen/Xanthotoxin | Small molecule - inhibits DNA synthesis | 10, 14, 20 | 10 | – | – | – |
| Noscapine | Antitussive | 14 | 10 (TC) | Hypotension, relaxation (Weaver et al., 1958; Manson et al., 2014) | – | 100 |
| Parthenolide | Antispasmodic | 10, 31, 46 | 1 (TC) | – | – | – |
| Pentagalloyl glucose (PGG) | Antitumorigenic | 5, 39 | 6.6 (EC50) | Modulates perivascular inflammation and prevents vascular dysfunction in Ang II-induced hypertension (mice) (Mikolajczyk et al., 2019) | 650 mg (65 kg human, 10 mg/kg i.p.) | ∼125 (without First Pass Effect)* |
| 1, 10-Phenanthroline | Antimicrobial | 5 | 100 (TC) | – | – | – |
| Picrotoxinin | Stimulant | 10, 14, 30, 46 | 18 (EC50) | AV block, ventricular premature contraction and/or ventricular tachycardia (rats) (Lee et al., 1972, 1974; Lin et al., 1992) | 1300 mg (65 kg human, 20 mg/kg i.v.) | ∼12* |
| Pirenzepine | Anticholinergic | 9 | 1800 (EC50) | Increased heart rate turbulence, augmented baroreceptor reflex sensitivity (Pedretti et al., 1995; Vukajlovic et al., 2006) | 50 mg/day | ∼25 (without First Pass Effect)* |
| Procainamide | Antiarrhythmic | 9 | 2800 (EC50) | Decrease contractility, hypertension, cardiovascular depression and collapse, prolonged PR/QT intervals and QRS complex, AV block, asystole, bundle branch block, ventricular premature contraction, ventricular tachycardia and ventricular fibrillation (Perkins and Marill, 2012; Ortiz et al., 2017; Osadchii, 2018) | 1300 mg (65 kg human, 10 mg/kg/20 min (i.v.) | ∼1000* |
| Quinine | Antimalarial | 4, 10, 14, 31, 39, 43, 46 | 10 (TC) | Hypotension, prolonged PR/QT intervals and QRS complex, bundle branch block, ventricular premature contraction, ventricular tachycardia and ventricular fibrillation (Danopoulos et al., 1954; Ortiz et al., 2017; Osadchii, 2018) | 10 mg/L | ∼31 |
| Salicin | Anti-inflammatory | 16 | 1400 ± 200 (EC50) | – | – | – |
| Salicylic acid | Derivative of aspirin | 14 | 1000 (TC) | Supraventricular tachycardia, prolonged asystole, atrial fibrillation (Mukerji et al., 1986; Ihama et al., 2007) | 0.49–1.1 mg/mL | ∼3500–8000 |
| Strychnine | Pesticide | 10, 46 | 0.43 ± 0.02 (EC50) | Cardiac arrest, bradycardia, ECG changes (Heiser et al., 1992; Wood et al., 2002; Ponraj et al., 2017) | 3.8 mg/L | ∼11 |
| 2-Thiouracil | Antithyroid | 4, 14, 46 | 100 ± 10 (EC50) | – | – | – |
| Tobramycin | Antibiotic | 14, 20 | 50.97 ± 19.37 (EC50) | Cardiodepression, hypotension, decreased CO, ventricular contractile force (dogs) (Adams et al., 1979) | 1300 mg (65 kg human, 20 mg/kg i.v.) | ∼500* |
| Yohimbine | Erectile dysfunction | 4, 10, 46 | 300 (TC) | Promote cardiac noradrenaline release (mice) (Wang et al., 2013) | 260 mg (65 kg human, 4 mg/kg) | >130 (without First Pass Effect)* |
| Endogenous factors | ||||||
| Alanine | α-Amino acid | 39 | 580 ± 10 (EC50) | – | – | – |
| Androsterone | Steroid hormone | 46 | 1 (TC) | – | – | – |
| Pantothenic acid | Vitamin B5 | 14, 31, 43 | 1000 (TC) | – | – | – |
| Progesterone | Steroid hormone | 46 | 3 (TC) | QTc shortening (double autonomic blockade, atropine and propranolol) - opposite effect of estradiol (Barbagallo et al., 2001; Yang et al., 2010; Salem et al., 2016; Barber et al., 2019) | 6500 μg (65 kg human, 100 μg/kg i.v.) | >3.5* |
| Taurocholic acid | Primary bile acid | 4 | 300 (TC) | Afterdepolarizations, atrial fibrillation, prolongation of contractile refractory period (Desai and Penny, 2013; Rainer et al., 2013) | – | 300–1000 |
| Bacterial toxins/metabolic by-products | ||||||
| Equol | Nonsteroid estrogen | 14, 39 | 100 | – | – | – |
| 4-Hydroxy-2-heptylquinolone (HHQ) | Pseudomonas aeruginosa quinolone | 14 | 100 | – | – | – |
| Homoserine lactone, N-butyryl-L- | Bacterial quorum sensing | 14 | 50 | – | – | – |
| Homoserine lactone, N-hexanoyl-L- | Bacterial quorum sensing | 10 | 2400 (TC) | – | – | – |
| Homoserine lactone, N-octanoyl-L- | Bacterial quorum sensing | 4, 14, 20 | 20 ± 10 (EC50) | – | – | – |
| Homoserine lactone, N-3-oxooctanoyl-L- | Bacterial quorum sensing | 4, 10, 14, 20 | 41 ± 13 (EC50) | Bradycardia (rats) (Gardiner et al., 2001) | 650 mg (65 kg human, 10 mg/kg i.v.) | >450* |
| Pseudomonas quinolone signal (PQS) | Pseudomonas aeruginosa quinolone | 4, 16, 39 | 100 | – | – | 150 (Morales-Soto et al., 2018) |