Table 2.
Experimental studies of cardioprotection via opioid receptor agonists applied prior to ischaemia
| Putative selectivity | Agent studied | Species, tissue | Primary outcome | Effect | Implicated effectors or targets | Study |
|---|---|---|---|---|---|---|
| Non-selective | Morphine | Rat, in situ heart | Infarct (TTC) | Improved | Neutrophil activity | Wang et al., 1998 |
| Infarct (TTC) | Improved | Gross et al., 2004a | ||||
| Rat, isolated heart | Infarct (TTC) | Improved | A1R, mKATP, ROS | Peart & Gross, 2003 | ||
| Infarct (TTC) | Improved | AMPK | Li et al., 2011 | |||
| DOR | TAN-67 (δ/δ1-receptor) | Rat, in situ heart | Infarct (TTC) | Improved | Gi/o, KATP | Schultz et al., 1998b |
| Infarct (TTC) | Improved | mKATP | Fryer et al., 1999 | |||
| Infarct (TTC) | Improved | PKCδ | Fryer et al., 2001 | |||
| Dog, in situ heart | Infarct (TTC) | Improved | Peart et al., 2003,2003 | |||
| DADLE | (δ/δ1 receptor) | Rat, isolated heart | CK leak, diastolic dysfunction | Improved | KATP | Kevelaitis et al., 1999 |
| Infarct (TTC) | Arrhythmogenesis | Improved Unaltered | Wang et al., 2001 | |||
| Infarct (TTC) | Improved | PKCε, Cx43 | Miura et al., 2007 | |||
| Rat, in situ heart | Infarct (TTC) | Improved | PKCδ | Fryer et al., 2001 | ||
| Infarct (TTC) | Arrhythmogenesis Mortality | Improved Unaltered | Gi/o, PKC, KATP | Valtchanova-Matchouganska & Ojewole. 2003 | ||
| Improved | ||||||
| Mouse, HL-1 cells | Necrosis | Improved | PKC, mKATP | Seymour et al., 2003 | ||
| Rabbit, isolated heart | Infarct (TTC) | Improved | EGFR/RTK | Cohen et al., 2007 | ||
| Human, atrial trabeculae | Contractility | Improved | mKATP | Bell et al., 2000 | ||
| BW-373U86 | Rabbit, in situ heart | Infarct (TTC) | Improved | δ1 receptor, COX-2 | Kodani et al., 2002 | |
| Dog, in situ heart | Infarct (TTC) | Improved | Peart et al., 2003,2003 | |||
| Rat, in situ heart | Infarct (TTC) | Improved | Gross et al., 2004a | |||
| Infarct (TTC) | Arrhythmogenesis | Improved Unaltered | Peart et al., 2004 | |||
| Mouse, isolated heart | Contractility | Improved | Peart & Gross 2004c | |||
| DPDPE (δ/δ1 receptor) | Pig, in situ heart | Infarct (TTC) | Improved | Sigg et al., 2002 | ||
| Rat, in situ heart | Infarct (TTC) | Improved | β2-adrenoceptor, intrinsic adrenergic cells | Huang et al., 2007a | ||
| Arrhythmogenesis | Unaltered | Maslov et al., 2014 | ||||
| Rat, neonate myocyte | Apoptosis | Unaltered | Shen et al., 2012 | |||
| Rat, in situ heart | Infarct (TTC) | Improved | 12-lipoxygenase | Patel et al., 2003 | ||
| Mouse, in situ heart | Infarct (TTC, cTnI) | Improved | Caveolin-3 | Tsutsumi et al., 2010 | ||
| SNC-121 | Rat, adult myocyte | Necrosis | Improved | Caveolae dependent | Patel et al., 2006 | |
| Deltorphin E (δ2 receptor) | Rat, neonate myocyte | Apoptosis | Improved | MEK/ERK1/2 | Shen et al., 2012 | |
| Rat, in situ heart | Infarct (TTC) | Improved | mKATP, sarcKATP | Patel et al., 2002b | ||
| Rat, in situ heart | Arrhythmogenesis | Improved | Peripheral δ2 receptors | Maslov et al., 2014 | ||
| Deltorphin-D (δ2 receptor) | Pig, in situ heart | Infarction (TTC) | Improved | PKC, NOS, mKATP | ||
| Rat, in situ heart | Arrhythmogenesis | Improved | Peripheral δ2 receptors | Maslov et al., 2014 | ||
| Deltorphin-II | (δ2 receptor) | Rat, in situ heart | Infarction | Improved | PKC, NOS, TK | Maslov et al., 2009 |
| Arrhythmogenesis | Improved | |||||
| Fentanyl isothiocyanate | (irreversible) | Rat, in situ heart | Infarction (TTC) | Improved | PI3K | Gross et al., 2005 |
| Infarction (TTC) | Improved | JAK2, STAT3, Akt, GSK3β | Gross et al., 2006 | |||
| KOR | Spiradoline | Rat, in situ heart | Arrhythmogenesis | Improved | Na+ channel block | Pugsley et al., 1998 |
| U50,488H | Rat, myocyte | Necrosis | Improved | HSP70 | Liu et al., 2004 | |
| Rat, isolated heart | Infarct (TTC) | Improved | PKC, mKATP | Wang et al., 2001 | ||
| Arrhythmogenesis | Improved | |||||
| Infarct (TTC) | Improved | mKATP, PKC, ROS | Cao et al., 2004 | |||
| Infarct (TTC) | Improved | PKC, KCa, mPTP | Cao et al., 2005 | |||
| Rat, in situ heart | Infarct (TTC) | Improved | Peart et al., 2004 | |||
| Arrhythmogenesis | Improved | |||||
| Infarct (TTC) | Improved | HSP70 | Qi et al., 2004 | |||
| Infarct (cTnT, CK, LDH ) | Improved | K+ current | Cheng et al., 2007 | |||
| Arrhythmogenesis | Improved | |||||
| Arrhythmogenesis | Improved | κ1 receptor, PKC, mKATP | Lishmanov et al., 2007 | |||
| Arrhythmogenesis | Improved | Cx43 | Zhang et al., 2010 | |||
| Infarct (TTC) | Improved | TLR4/TNF-α | Lin et al., 2013 | |||
| Rat, in situ and mouse, isolated heart | Infarct (TTC) | Improved | PI3K, mKATP | Peart et al., 2008 | ||
| Mouse, isolated heart | Contractility | Improved | Peart & Gross 2004c | |||
| Dynorphin B | Rabbit, myocyte | Necrosis | Improved | PKC, KATP | Cao et al., 2003 | |
| MOR | DAMGO | Rat, in situ heart | Infarct (TTC) | Unaltered | Schultz et al., 1998a | |
| Arrhythmogenesis | Unaltered | Maslov et al., 2014 | ||||
| Fentanyl | Rat, isolated heart | Contractility | Improved | mKATP, A1 receptor | Kato et al. 2000 | |
| Rabbit, in situ heart | Infarct (TTC) | Improved | Peripheral opioid receptors | Lessa & Tibiriçá, 2006 | ||
| Arrhythmogenesis | Improved | Central opioid receptors | ||||
| Remifentanil | Rat, in situ heart | Infarct (TTC) | Improved | Zhang et al., 2004 | ||
| Infarct (TTC) | Improved | ERK1/2, Bcl2, Bax | Kim et al., 2010 | |||
| Remifentanil Sufentanil | Human, atrial trabeculae | Contractile recovery | Improved | Lemoine et al., 2011 | ||
| MOR/DORs | Eribis peptide 94 | Rat, in situ heart | Infarct (TTC) | Improved | Central MORs | Gross et al., 2012a |
Shown are the effects of pre-ischaemic opioid receptor agonists on outcomes from myocardial I–R in experimental animal models and ex vivo human tissue. Outcomes include infarction/cell death (via TTC staining, release of intracellular proteins, or markers of isolated cell viability), contractile recovery, and arrhythmogenesis. Also shown are the receptors, signalling elements or effector molecules implicated in protection (where assessed). AMPK, 5′ AMP-activated PK; BW373U86, 4-[(R)-[(2S,5R)-2,5-dimethyl-4-prop-2-enylpiperazin-1-yl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide; CK, creatine kinase; Cx43, connexin-43; cTnI, cardiac Troponin I; cTnT, cardiac troponin T; DADLE, [d-Ala2, d-Leu5] enkephalin; DAMGO, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DPDPE, D-penicillamine(2,5)-enkephalin; GSK3β, glycogen synthase kinase 3β; MEK, MAPK kinase; mKATP, mitochondrial KATP channel; sarcKATP, sarcolemmal KATP channel; SNC-80, 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide; SNC-121, 4-((aR)-a-((2S,5R)-4-Propyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; TAN-67, [(4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12, 12a -octahydropyrido[3,4-b]acridine; TLR4, toll-like receptor 4; TTC, 2,3,5-triphenyl-2H-tetrazolium chloride staining for infarction; U50,488H, [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide].