Heptanol triggers cardioprotection via mitochondrial mechanisms and mitochondrial potassium channel opening in rat hearts.

Abstract

AIM:

To investigate mechanisms behind heptanol (Hp)-induced infarct size reduction and in particular if protection by pre-treatment with Hp is triggered through mitochondrial mechanisms.

METHODS:

Langendorff perfused rat hearts, isolated mitochondria and isolated myocytes were used. Infarct size, mitochondrial respiration, time to mitochondrial permeability transition pore (MPTP) opening and AKT and glycogen synthase kinase 3 beta (GSK-3β) phosphorylation were examined.

RESULTS:

Pre-treatment with Hp reduced infarct size from 29.7 ± 3.4% to 12.6 ± 2.1%. Mitochondrial potassium channel blockers 5-hydroxy decanoic acid (5HD) blocking mitoK(ATP) and paxilline (PAX) blocking mitoK(Ca) abolished cardioprotective effect of Hp (Hp + 5HD 36.7 ± 2.9% and Hp + PAX 40.2 ± 2.8%). Hp significantly reduced respiratory control ratio in both subsarcolemmal and interfibrillar mitochondria in a dose-dependent manner (0.5-5.0 mm). The ADP oxygen ratio was also significantly reduced by Hp (2 mm). Laser scanning confocal microscopy of tetramethylrhodamine-loaded isolated rat myocytes using line scan mode showed that Hp increased time to MPTP opening. Western blot analysis showed that pre-treatment with Hp increased phosphorylation of AKT and GSK-3β before ischaemia and after 30 min of global ischaemia.

CONCLUSION:

Pre-treatment with Hp protects the heart against ischaemia-reperfusion injury. This protection is most likely mediated via mitochondrial mechanisms which initiate a signalling cascade that converges on inhibition of opening of MPTP.

• Authors: D Johansen, E Sanden, M Hagve, X Chu, R Sundset, K Ytrehus
• Journal: Acta physiologica (Oxford, England) (Acta Physiol (Oxf)) Vol. 201 Issue 4 Pg. 435-44 (Apr 2011) ISSN: 1748-1716 [Electronic] England
• PMID: 21070611 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Potassium Channels
• mitochondrial K(ATP) channel
• Heptanol

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Cells, Cultured
• Female
• Heptanol (pharmacology)
• Male
• Mitochondria, Heart (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore
• Myocardial Infarction (pathology)
• Myocardium (cytology, metabolism, pathology)
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Potassium Channels (metabolism)
• Rats
• Rats, Wistar