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Am J Physiol Heart Circ Physiol (May 1, 2003). doi:10.1152/ajpheart.01004.2002
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Submitted on November 21, 2002
Accepted on April 28, 2003

Activation of {delta}- and {kappa}-Opioid Receptors by Opioid Peptides Protects Cardiomyocytes via KATP Channels

Zhiping Cao1, Lijuan Liu1, and Donna M Van Winkle2*

1 Department of Anesthesiology Service, Veterans Affairs Medical Center, Portland, OR, USA
2 Department of Anesthesiology Service, Veterans Affairs Medical Center, Portland, OR, USA; Department of Research Service, Veterans Affairs Medical Center, Portland, OR, USA; Department of Anesthesiology, Oregon Health and Science University, Portland, OR, USA

* To whom correspondence should be addressed. E-mail: donna.vanwinkle{at}med.va.gov.

To examine receptor specificity and mechanism of opioid peptide-induced protection, we examined freshly isolated adult rabbit cardiomyocytes subjected to simulated ischemia. Cell death as a function of time was assessed by trypan blue permeability. Dynorphin B (Dyn B) and Met5-enkephalin (ME) limitation of cell death (expressed as area under the curve) was sensitive to blockade by both naltrindole (NTI, {delta}-selective antagonist) and GNTI dihydrochloride (GNTI, {kappa}-selective antagonist): Dyn B 85.7 ± 2.7, Dyn B + NTI 142.9 ± 2.7, P<0.001; Dyn B 94.1 ± 4.2, Dyn B + GNTI 164.5 ± 7.3, P<0.001; ME 111.9 ± 7.0, ME + NTI 192.1 ± 6.4, P<0.001; ME 120.2 ± 4.3, ME + GNTI 170.0 ± 3.3, P<0.001). Blockade of KATP channels eliminated Dyn B and ME-induced protection: CON 189.6 ± 5.4, ME 139.0 ± 5.4 P<0.001; 5HD 210 ± 5.9, ME + 5HD 195 ± 6.1, P<0.001; and CON 136.0 ± 5.7, ME 63.4 ± 5.4, P<0.001; HMR 1098 144.6 ± 4.5, ME + HMR 1098 114.6 ± 7.7, P<0.01; CON 189.6 ± 5.4, ME 139.0 ± 5.4 P<0.001; 5HD 210 ± 5.9, ME + 5HD 195 ± 6.1, P<0.001; and CON 136.0 ± 5.7, ME 63.4 ± 5.4, P<0.001; HMR 1098 144.6 ± 4.5, ME + HMR 1098 114.6 ± 7.7, P<0.01. We conclude that opioid peptide-induced cardioprotection is mediated by {delta}- and {kappa}-receptors and involves both sarcolemmal and mitochondrial KATP channels.




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