Delayed ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart

Abstract

Cardioprotection from preconditioning reappears 24 h after the initial stimulus. This phenomenon is called the second window of protection (SWOP). We hypothesized that opening of the ATP-sensitive potassium (KATP) channel mediates the protective effect of SWOP. Rabbits were preconditioned (PC) with four cycles of 5-min regional ischemia each followed by 10 min of reperfusion. Twenty-four hours later, the animals were subjected to sustained ischemia for 30 min followed by 180 min of reperfusion (I/R). Glibenclamide (Glib, 0.3 mg/kg ip) or 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was used to block the KATP channel function. Infarct size was reduced from 41.2 ± 2.6% in sham-operated rabbits to 11.6 ± 1.0% in PC rabbits, a 71% reduction ( n = 11, P < 0.01). Treatment with Glib or 5-HD before I/R increased the infarct size to 43.4 ± 2.6 and 37.8 ± 1.9%, respectively ( P < 0.01 vs. PC group, n = 12/group). Sham animals treated with either Glib or 5-HD had an infarct size of 39.0 ± 3.4 and 37.8 ± 1.5%, respectively, which was not different from control (40.0 ± 3.8%) or sham (41.2 ± 2.6%) I/R hearts. Monophasic action potential duration (APD) at 50% repolarization significantly shortened by 28.7, 26.6, and 23.3% in sham animals during 10, 20, and 30 min of ischemia. However, no further augmentation in the shortening of APD was observed in PC hearts. Glib and 5-HD significantly suppressed ischemia-induced epicardial APD shortening, suggesting that 5-HD may not be a selective blocker of the mitochondrial KATP channel in vivo. We conclude that SWOP is mediated by a KATP channel-sensitive mechanism that may have occurred because of the opening of the sarcolemmal KATP channel in vivo.

Gene Transfer of Heat-Shock Protein 70 Reduces Infarct Size In Vivo After Ischemia/Reperfusion in the Rabbit Heart

“…8,26b This is because the acquisition of cardiac resistance to ischemia after ischemic preconditioning or heat shock is a multifactorial phenomenon that includes several other possible mechanisms besides the induction of Ն1 members of the heat-shock protein family. These include the activation of protein kinase C, 27,28 receptor tyrosine kinase, 29 stressactivated MAPKAP kinase 2, 30 nuclear factor-B, 31 nitric oxide synthase(s), 32,33 antioxidant defense systems such as increased activities of SOD 34 and catalase, 35 opening of ATP-sensitive potassium channels, 15,36 or possibly other unknown mechanisms. Some of the above mediators may have a role in signaling pathways leading to the synthesis of Ն1 of the protective proteins, including HSP 70.…”

Mitochondrial ATP-Sensitive Potassium Channels Attenuate Matrix Ca 2+ Overload During Simulated Ischemia and Reperfusion

“…IPC exists in all species examined, including humans. 2 Mitochondrial K ATP (mitoK ATP ) channels feature prominently in the mechanism of cardioprotection [3][4][5][6][7][8][9] ; however, their precise role remains controversial. A decrease in the extent of mitochondrial Ca 2ϩ overload during ischemia and reperfusion (I/R) has been proposed to prevent or delay cell death, 10,11 and activation of the mitochondrial permeability transition (MPT) may be involved in this process.…”

Two Novel Approaches Providing Cardiac Protection Against Oxidative Stress

“…Downstream events include phosphorylation of STAT1/3 and activation of STAT dependent genes which include the COX-2 gene. Other events that mediate late preconditioning include NO release (through a PKG dependent mechanisms and opening of mitochondrial K(ATP) channels (Bernardo et al, 1999;Ockaili et al, 1999). It has been reported that the NO that mediates late preconditioning is derived from inducible NOS (iNOS).…”