Cardioprotective profile of MET‐88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts

Abstract

3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) application of insulin (500 muU/mL) in the perfusate (insulin); and 4) pretreatment with MET-88 and application of insulin (MET-88 + insulin). MET-88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 min period under normoxia, followed by a 30 min period under hypoxia. Hearts were frozen at the end of hypoxia for the measurement of high-energy phosphates, carnitine derivatives, and glycolysis intermediates. In a separate series of untreated and MET-88 treated hearts, exogenous glucose and palmitate oxidation was measured. MET-88 decreased the extent of the depression of cardiac contractility (+dP/dt), and aortic flow during the hypoxic state. Insulin also improved cardiac function, and co-treatment of MET-88 and insulin additionally improved cardiac function during hypoxia. MET-88 prevented the decrease of high-energy phosphate and the increase of long-chain acylcarnitine after 30 min of hypoxic perfusion. In addition, MET-88 increased the steady state of glucose oxidation in hypoxic perfused rat hearts. These results indicate that MET-88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic condition. Preventing the accumulation of long-chain acylcarnitine may serve to protect hypoxic hearts.

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

“…Основным воздействием милдроната на метаболизм считается ингибирование бета-окисления жирных кислот, что способствует потреблению глюкозы [5,13,21]. Схема на рисунке 3 поясняет этот механизм.…”

“…В экспериментальных исследованиях милдронат 490 * -адресат для переписки оказывал влияние на потребление глюкозы и метаболизм кетоновых тел, стимулировал инсулин-зависимое потребление глюкозы [10][11][12]. Показано также, что милдронат ускоряет окисление глюкозы в сердцах крыс при гипоксии [13]. Препарат защищает и от токсического действия других соединений.…”

Cardioprotective Effects of MET-88, a Gamma-Butyrobetaine Hydroxylase Inhibitor, on Cardiac Dysfunction Induced by Ischemia/Reperfusion in Isolated Rat Hearts

“…Simkhovich et al [9] reported that MET-88 reduced the levels of intracellular free carnitine, long-chain acylcarnitine and long-chain acyl-CoA. Also, previous study demonstrated that MET-88 improved energy metabolism in the ischemic canine heart and cardiac function in the isolated perfused rat heart under hypoxia [10][11][12]. Thus, we postulated that MET-88 may attenuate the deleterious effects of ischemia with severe oxygen depletion.…”

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

“…11,12 It is suggested that mildronate's protective action is based on its ability to inhibit carnitine palmityoiltransferase-1 activity thus decreasing the amount of activated FFAs in mitochondria. 9 Since activated FFAs possess detergentlike activity damaging mitochondrial membranes, we suggest that mitochondria may serve as the target for midronate's cytoprotective action.…”

“…10 Furthermore, it was also shown that mildronate decreases the concentration of lactic acid and increases ATP level in cardiac tissue after coronary artery occlusion; 11 as well as preventing the drop of ATP content during hypoxia of isolated rat heart . 12 A plausible mechanism to explain mildronate's protective action is related to its ability to regulate carnitine levels by acting as a competitive inhibitor of gammabutyrobetaine (GBB) hydroxylase, 13,14 thus inhibiting GBB transformation to carnitine. In fact, in rat liver mitochondria, mildronate was found to inhibit carnitine-palmitoyltransferase-1, thus protecting against long-chain fatty acid accumulation and subsequent damage of mitochondrial membranes.…”