title: 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.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Janis
authors.initials: J
authors.lastname: Kuka
authors.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Marina
authors.initials: M
authors.lastname: Makrecka-Kuka
authors.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Helena
authors.initials: H
authors.lastname: Cirule
authors.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Eduards
authors.initials: E
authors.lastname: Sevostjanovs
authors.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.|Faculty of Pharmacy, Riga Stradins University, Riga, Latvia.
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
authors.affiliation: Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
mesh_terms: D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D001711:Biotransformation; D002316:Cardiotonic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006207:Half-Life; D006321:Heart / Q000187:drug effects*; D008297:Male; D049990:Membrane Transport Modulators / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008970:Molecular Weight; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D017208:Rats, Wistar; D000074058:Solute Carrier Family 22 Member 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002316:Cardiotonic Agents; D049990:Membrane Transport Modulators; D000644:Quaternary Ammonium Compounds; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; C116917:acylcarnitine; C000602882:methyl-gamma-butyrobetaine; D001622:Betaine; C002889:gamma-butyrobetaine; D005680:gamma-Aminobutyric Acid; D002331:Carnitine