Decrease in Long-Chain Acylcarnitine Tissue Content Determines the Duration of and Correlates with the Cardioprotective Effect of Methyl-GBB.

Abstract

Ischaemia in the heart is accompanied by the accumulation of long-chain acylcarnitines (LCACs) which is one of the multiple factors that contribute to the ischaemia-reperfusion damage development. Long-term pre-treatment that decreases carnitine and LCAC contents also reduces ischaemia-reperfusion (IR) damage; however, the duration of the post-treatment effects is not known. The aim of the study was to assess the post-treatment effects of the carnitine transport (OCTN2) inhibitor, methyl-GBB, on LCAC content and the duration of its cardioprotective effect. Male Wistar rats received methyl-GBB (5 mg/kg for 28 days), and the anti-infarction effects on Langendorff-perfused hearts and the acylcarnitine profile in cardiac tissues were measured up to 28 days following the end of the treatment. Methyl-GBB pre-treatment for 28 days decreased LCAC heart tissue content by 87%, and the infarct size was decreased by 57%. Fourteen days post-treatment, the LCAC content was still decreased by 69%, and the infarct size was decreased by 32% compared to Control. A significant Pearson correlation (r = 0.48, p = 0.026) was found between infarct size and LCAC tissue content in the methyl-GBB-treated rat hearts. The addition of 2 mM carnitine to isolated heart perfusate significantly diminished the methyl-GBB-induced decrease in LCACs and infarct size. In conclusion, the anti-infarction effect of methyl-GBB continues for at least 2 weeks post-treatment. No less than a 70% decrease in LCAC content is required to protect ischaemic heart tissues, and the decrease in LCAC levels defines the duration of the post-treatment cardioprotective effect of the OCTN2 inhibitor, methyl-GBB.

• Authors: Janis Kuka, Marina Makrecka-Kuka, Helena Cirule, Solveiga Grinberga, Eduards Sevostjanovs, Maija Dambrova, Edgars Liepinsh
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 121 Issue 2 Pg. 106-112 (Aug 2017) ISSN: 1742-7843 [Electronic] England
• PMID: 28244203 (Publication Type: Journal Article)
• Copyright: © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Chemical References

• Cardiotonic Agents
• Membrane Transport Modulators
• Quaternary Ammonium Compounds
• Slc22a5 protein, rat
• Solute Carrier Family 22 Member 5
• acylcarnitine
• methyl-gamma-butyrobetaine
• Betaine
• gamma-butyrobetaine
• gamma-Aminobutyric Acid
• Carnitine

Topics

• Animals
• Betaine (analogs & derivatives, blood, metabolism)
• Biotransformation
• Cardiotonic Agents (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Carnitine (analogs & derivatives, blood, chemistry, metabolism)
• Down-Regulation (drug effects)
• Half-Life
• Heart (drug effects)
• Male
• Membrane Transport Modulators (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Molecular Weight
• Myocardial Infarction (metabolism, prevention & control)
• Myocardium (metabolism)
• Perfusion
• Quaternary Ammonium Compounds (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Random Allocation
• Rats, Wistar
• Solute Carrier Family 22 Member 5 (antagonists & inhibitors, metabolism)
• Time Factors
• Tissue Distribution
• gamma-Aminobutyric Acid (analogs & derivatives, metabolism, pharmacokinetics, pharmacology, therapeutic use)