Abstract 1704: Decreased Cardiac Methionine-Enkephalin and Opioid Peptide Receptor Expression in End-Stage Human Heart Failure
Opioids counter norepinephrine effects via G-protein-coupled receptors (OPR) to mediate bradycardia, negative inotropy, vasodilation, blood pressure reduction and trigger cardioprotective intracellular signal transduction. Enkephalins are coreleased with norepinephrine from sympathetic neurons terminating in the heart in addition to local myocardial cell synthesis.
Aims: As OPR are not well defined in human heart failure, we tested whether OPR expression in end-stage heart failure (HF) differs from non-failing donor (NFD). Cardiac methionine-enkephalin (ME) content, the major end-product of cardiac proenkephalin, was also determined.
Methods: mRNA and protein expression in NFD (n=10) and HF (n=12) for μ-, δ- and κ-OPR were assessed by realtime PCR and polyclonal antibody-based immunofluorescence protocols using homogenates and frozen sections. OPR-specific fluorescence was visualized via confocal microscopy and quantified by stereology. For each heart chamber, 30 separate sections (120 per heart) were assessed and averaged. ME was measured by I125-radioimmunoassay.
Results: δ- and κ-OPR were localised on myocyte sarcolemma. In NFD, δ-OPR fluorescence was greatest in the right heart, particularly the right atrium (RA>RV>LA>LV). δ-OPR values were lower in all HF chambers compared to NFD, p=0.0006 (by 49±4%, 36±3%, 22±2%, 40±3%, for RA, RV, LA, LV, respectively). κ-OPR were 25±2% more abundant in RV from NFD than in HF (p<0.0001) and LA, LV and RA from NFD and HF. The magnitude of mRNA expression was comparable to protein expression, with κ-OPR being more abundant than δ-OPR in NFD and both κ- and δ-OPR were diminished in all HF chambers. μ-OPR were evident only on cells of the coronary microvasculature from NFD and HF tissue and negligible mRNA for μ-OPR was detected in any heart. Cardiac ME content was lower in HF hearts compared to NFD (pg/g tissue: LA: 777±910 vs 1564±953, p=0.09; RA: 1194±1700 vs 1789±1307, p=0.17; LV:606±438 vs 1257±627, p=0.01; RV: 518±310 vs 1822±1227, p=0.002).
Conclusion: The failing human heart with ischemic and other etiology has a distinct reduction in δ- and κ-OPR expression and ME content. The present data support a reduced capacity for opioid-dependent regulation and cardioprotection in the failing heart.