Chronic preconditioning: a novel approach for cardiac protection

Abstract

Ischemic preconditioning is the most powerful protective mechanism known against lethal ischemia. Unfortunately, the protection lasts for only a few hours. Here we tested the hypothesis that the heart can be kept in a preconditioned state for constant protection against ischemia. In this study we chose BMS-191095 (BMS), a highly selective opener of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. BMS (1 mg/kg ip) was administered to rats every 24 h until 96 h. In other groups, BMS plus wortmannin (WTN, 15 microg/kg ip), an inhibitor of the phosphatidylinositol 3-kinase (PI3-K), or BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK(ATP), or BMS plus N(omega)-nitro-L-arginine methyl ester (L-NAME) (30 microg/kg ip), an inhibitor of nitric oxide (NO) synthase, were administered to rats. Rats were then subjected to 30-min left anterior descending coronary artery occlusion and 120-min reperfusion. Cardiac function, infarct size, pathological changes, and apoptosis were assessed at the end of treatments. Saline-treated hearts displayed marked contractile dysfunction and underwent pathological changes. BMS-treated rats showed significant improvement in cardiac function, and infarct size was significantly reduced in BMS-treated hearts. However, protection by BMS was abolished by 5-HD, WTN, or L-NAME. These data demonstrate that hearts can be chronically preconditioned and retain their ability to remain resistant against lethal ischemia and that this protection is mediated by activation of mitoK(ATP) via NO and PI3-K/Akt signaling pathways.

KR-31761, a Novel K+ATP-Channel Opener, Exerts Cardioprotective Effects by Opening Both Mitochondrial K+ATP and Sarcolemmal K+ATP Channels in Rat Models of Ischemia/Reperfusion-Induced Heart Injury

“…The results from studies with 5-HD and glyburide also do not rule out the effect of KR-31761 on the sarcK proposed based on a strong rationale that mitochondria act as the organelle of death or life, the role of mitoK + ATP channel in preserving structure and function of mitochondria has been associated with its beneficial effects including non-arrythmogenicity, decrease in mitochondrial Ca 2+ accumulation and apoptosis, and augmented synthesis of ATP (3). Recent findings that a highly selective mitoK + ATP -channel opener BMS-191095 could induce chronic preconditioning in which the heart can be kept in a preconditioned state for an extended period of time (days or weeks) in anticipation of cardiac surgery may render utilization of a mitoK + ATP -channel opener a novel approach for cardiac protection (26). According to more recent studies, opening of the mitoK + ATP channel leads to increase in pH and H 2 O 2 (ROS) production, which in turn activates PKCε2 associated with the inner membrane of mitochondria, resulting in inhibition of Ca…”

“…Since the discovery of BMS-180448 as the first cardioselective K + ATP -channel opener with markedly reduced vasorelaxant activity over cromakalim, pinacidil, and other potassium channel openers of the first generation (14,15), a few cardioselective mitoK + ATP -channel openers, including BMS-191095 and KR-31378, have been developed and proved to have improved pharmacological profile for the treatment of myocardial ischemia (16 -20), neuronal ischemia (21 -25), and cardiac hypertrophy (17). It appears quite intriguing to find out that intermittently administered cardioselective mitoK + ATP opener BMS-191095 could keep rat hearts preconditioned against ischemia / reperfusion heart injury for an extended period of time (days), raising the promising utilization of mitoK + ATP openers for chronic pharmacological preconditioning (3,26).…”

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…Myocardial infarction (MI) model was developed in SD female rats (200-250 g), as previously described [8]. Briefly, Isoflurane anesthesia was induced by spontaneous inhalation.…”

Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction

“…A MI model was developed in female SD rats (200 -250 g), as previously described (32). Briefly, isoflurane anesthesia was induced by spontaneous inhalation.…”