Accumulation of long chain fatty acids decreases the cardioprotective effect of KATP channel openers

Abstract

The oxidation of fatty acids serves as the main energy source for cardiomyocytes. However, in ischemic tissue fatty acid oxidation is inhibited, resulting in accumulation of long chain fatty acids and their CoA derivatives. In this study, we investigated the influence of fatty acids on the effects of KATP channel openers on isolated rat heart mitochondria. Mitochondrial respiration rates were recorded by the means of Clark-type oxygen electrode in the isotonic KCl medium (37 °C), using pyruvate and malate (6–6 mm) or fatty acids - palmitoyl-L-carnitine (9 mkm) and malate (240 mkm) or palmitoyl-CoA (5 mkm; + L-carnitine (2 mm)) and malate (240 mkm) as substrates. The results showed that KATP channel openers diazoxide (300 mkm) and pinacidil (300 mkm) similarly increased (by ~100%) the state 2 respiration rate of mitochondria, oxidizing either pyruvate and malate or fatty acids. In contrast, when palmitoyl-CoA (2.5 mkm) was not oxidized (medium devoid of carnitine), it suppressed the uncoupling effect of KATP channel openers in mitochondria, respiring on pyruvate and malate. Thus, during ischemia, the effects of KATP channel openers could decrease due to accumulation of physiological inhibitor of adenine nucleotide translocase - palmitoyl-CoA. Since uncoupling is proposed as one of the mechanisms of pharmacological cardioprotection, our results suggest that higher concentrations of KATP channel openers might be required to protect cardiomyocytes from ischemic injuries