Extending the cardioprotective window using a novel δ-opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway

Gross, Eric R.; Peart, Jason Nigel John; Hsu, Anna; Auchampach, John A.; Gross, Garrett J.

doi:10.1152/ajpheart.00918.2004

Cited by 45 publications

(29 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the effectiveness of ARD-353 as a cardioprotective agent has been demonstrated in the rat model of myocardial infarct in two laboratories and the scale of effect in this model agrees well with that reported in other laboratories (Schultz et al, 1998;Fryer et al, 1999;Gross et al, 2005), there is little support for, or against, a direct correlation between efficacy in the rodent models of myocardial ischemia and efficacy in clinical studies across compound classes. As specific test populations are described more explicitly, and so-called surrogate measures for myocardial damage are validated as early measures in place of long, large-scale mortality studies, so more data on the efficacy of compounds and the correlation with preclinical data are anticipated.…”

Section: Discussionsupporting

confidence: 68%

“…The cardioprotective effects of ARD-353 have only been challenged in a short-term dosing setting to date, and the complexities of the opioid receptor versus a nonreceptor-mediated effect in the delayed protection seen with ARD-353 will be examined in future studies. As shown by Gross et al (2005) with the ␦-selective agonist, fentanyl isothiocyanate, ARD-353 was still cardioprotective when administered immediately postocclusion. This effect, combined with the lack of any measurable central effects, may indicate a critical component of the clinical utility of ARD-353 in an emergency setting after a myocardial infarction event.…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

ARD-353 [4-((2R,5S)-4-(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic Acid], A Novel Nonpeptide δ Receptor Agonist, Reduces Myocardial Infarct Size without Central Effects

Watson¹,

Holt²,

O'Neill³

et al. 2005

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

A novel ␦-receptor selective compound, 5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2, 5-dimethylpiperazin-1-ylmethyl)benzoic acid], was evaluated for activity on infarct size in a rat model of acute myocardial infarction. ARD-353 was characterized as having ␦ receptor selectivity using radioligand binding and had no apparent selectivity between ␦ receptor subtypes as determined by and then subjected to 30 min of LAD occlusion followed by 90 min of reperfusion, infarct size was reduced in a dose-dependent manner compared with vehicletreated controls. The effects of ARD-353 on infarct size were blocked by the ␦ 1 -opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the ␦ 1 -opioid receptor in the cardioprotective mechanism of ARD-353. ARD-353 (0.3 mg/kg i.v.) produced significant protection when administered 5 min and 12 and 48 h before ischemic insult or when given immediately after the ischemic insult (at the start of reperfusion). Given the lack of central nervous system effects and beneficial efficacy in the rat model of myocardial ischemia, it is felt that ARD-353 is the first nonpeptide ␦-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.Ischemic preconditioning (IPC) is a physiological method of reducing injury to the myocardium after short-term ischemia and reperfusion that has demonstrated some potential for clinical efficacy (Murry et al., 1986). Repeated cycling of short episodes of ischemia induces changes in the myocardial cell signaling systems that seem to condition the myocytes to be resistant to ischemic and reperfusion damage. The ATPsensitive potassium channel (Gross and Auchampach, 1992), G i proteins (Lasley and Mentzer, 1993;Thornton et al., 1993), protein kinase C (Ytrehus et al., 1994), and the Na ϩ /H ϩ exchanger (Rohmann et al., 1995;Bugge et al., 1996;Piper et al., 1996) have all been implicated as part of the cellular mechanism of ischemic preconditioning. In addition to these messenger systems, several receptors have been Article, publication date, and citation information can be found at

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 91%

ARD-353 [4-((2R,5S)-4-(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic Acid], A Novel Nonpeptide δ Receptor Agonist, Reduces Myocardial Infarct Size without Central Effects

Watson¹,

Holt²,

O'Neill³

et al. 2005

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…Proteins involved in SLP also differ from those in delayed PC, because the latter is NO-and potentially K ATP channeldependent (Baxter and Ferdinandy, 2001), whereas SLP is not (Peart and Gross, 2006). The longevity of protection with SLP is uncommon outside of genetic manipulation, although irreversible ␦-opioid agonism affords protection for up to 5 days (Gross et al, 2005). Paralleling SLP, this response is abolished by coadministration of wortmannin, whereas PI3K inhibition during ischemia is only partially inhibitory (Gross et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The longevity of protection with SLP is uncommon outside of genetic manipulation, although irreversible ␦-opioid agonism affords protection for up to 5 days (Gross et al, 2005). Paralleling SLP, this response is abolished by coadministration of wortmannin, whereas PI3K inhibition during ischemia is only partially inhibitory (Gross et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

Peart¹,

Hoe²,

Gross³

et al. 2010

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

We have previously described novel cardioprotection in response to sustained morphine exposure, efficacious in young to aged myocardium and mechanistically distinct from conventional opioid or preconditioning (PC) responses. We further investigate opioid-dependent sustained ligand-activated preconditioning (SLP), assessing duration of protection, opioid receptor involvement, additivity with conventional responses, and signaling underlying preischemic induction of the phenotype. Male C57BL/6 mice were treated with morphine (75-mg subcutaneous pellet) for 5 days followed by morphine-free periods (0, 3, 5, or 7 days) before ex vivo assessment of myocardial tolerance to 25-min ischemia/45-min reperfusion. SLP substantially reduced infarction (by ϳ50%) and postischemic contractile dysfunction (eliminating contracture, doubling force development). Cardioprotection persisted for 5 to 7 days after treatment. SLP was induced specifically by ␦-receptor and not -or -opioid receptor agonism, was eliminated by ␦-receptor and nonselective antagonism, and was additive with adenosinergic but not acute morphine-or PC-triggered protection. Cotreatment during preischemic morphine exposure with the phosphoinositide-3 kinase (PI3K) inhibitor wortmannin, but not the protein kinase A (PKA) inhibitor myristoylated PKI-(14-22)-amide, prevented induction of SLP. This was consistent with shifts in total and phospho-Akt during the induction period. In summary, data reveal that SLP triggers sustained protection from ischemia for up to 7 days after stimulus, is ␦-opioid receptor mediated, is induced in a PI3K-dependent/PKA-independent manner, and augments adenosinergic protection. Mechanisms underlying SLP may be useful targets for manipulation of ischemic tolerance in young or aged myocardium.

show abstract

“…with dmso 1%, wortmannin 15 µg/kg [24] and chelerythrine 5 mg/kg [25] respectively, 10 min prior to N or IH.…”

Section: Treatment Groupsmentioning

confidence: 99%

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

Béguin

Belaidi

Godin‐Ribuot

et al. 2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2.. Journal of Molecular and Cellular Cardiology, Elsevier, 2007, 42 (2) AbstractObjective. We previously reported that acute intermittent hypoxia (IH) confers delayed cardioprotection against a prolonged ischemic insult in the rat, via the involvement of nitric oxide synthase and K ATP channels. In the present study, we investigated the role of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), stress activated p38 MAP kinase (MAPK) and extracellular signal regulated kinase (ERK1/2) using selective inhibitors of these pathways. Methods. Adult male rats were exposed to 1-min cycles of IH (10% O 2 , 40 sec) / normoxia (21% O 2 , 20 sec) during 4 hrs or to normoxic cycles. 24 hrs later, isolated hearts were perfused in Langendorff mode and subjected to a 30-min global ischemia followed by 120 min of reperfusion. Results. Compared to normoxic conditions, IH significantly reduced infarct size (22.2  2.4% vs 33.8  2.6%, p<0.05), improved coronary flow and decreased the contracture at reperfusion. When administered before sustained ischemia, chelerythrine (a PKC inhibitor) abolished both the IH-induced reduction in infarct size (36.1  4.9%) and improvement in hemodynamic parameters. In contrast, chelerythrine administration 10 min before IH, did not modify the delayed cardioprotective response. Similarly, wortmannin (a PI3K inhibitor) administration 10 min before IH was unable to block the cardioprotective effects. However, administration of SB203580 (a p38 MAPK inhibitor) and PD98059 (an Erk1/2 inhibitor), 30 min before IH abolished its delayed infarct-sparing effect (32.2  3.4% and 33.9  2.9% respectively). In addition, 24 hrs after IH, a significant increase in p38 MAPK and Erk1/2 phosphorylation was observed by Western blot. Conclusion. These results suggest that the delayed preconditioning induced by intermittent hypoxia does not involve the PI3K signalling pathway and that is mediated by PKC and triggered by p38 MAPK and Erk1/2.

show abstract

Extending the cardioprotective window using a novel δ-opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway

Cited by 45 publications

References 44 publications

ARD-353 [4-((2R,5S)-4-(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic Acid], A Novel Nonpeptide δ Receptor Agonist, Reduces Myocardial Infarct Size without Central Effects

ARD-353 [4-((2R,5S)-4-(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic Acid], A Novel Nonpeptide δ Receptor Agonist, Reduces Myocardial Infarct Size without Central Effects

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

Contact Info

Product

Resources

About