Ischemic preconditioning in rats: role of mitochondrial K_ATPchannel in preservation of mitochondrial function

Abstract

We examined the role of the sarcolemmal and mitochondrial K(ATP) channels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 +/- 1%) versus control (56 +/- 1%). The sarcolemmal K(ATP) channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial K(ATP) channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 +/- 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 +/- 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 +/- 0.30 micromol x min(-1) x mg mitochondrial protein(-1). Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 +/- 0.06 micromol x min(-1) x mg mitochondrial protein(-1). IPC significantly increased ATP synthesis to 1.86 +/- 0.23 micromol x min(-1) x mg mitochondrial protein(-1). However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 +/- 0.15 micromol x min(-1) x mg mitochondrial protein(-1)). These data are consistent with the notion that inhibition of mitochondrial K(ATP) channels attenuates IPC by reducing IPC-induced protection of mitochondrial function.

Cardioprotective Effect of Diazoxide Is Mediated by Activation of Sarcolemmal but Not Mitochondrial ATP-Sensitive Potassium Channels in Mice

“…In this context, it is noteworthy that in rat, cardioprotective doses of diazoxide did not shorten APD during ischemia, and the cardioprotection by diazoxide was blocked by 5-HD but not by HMR1098. 4,7 Therefore, the findings obtained from mouse hearts cannot be directly extrapolated to clinical settings.…”

“…In this context, it is noteworthy that in rat, cardioprotective doses of diazoxide did not shorten APD during ischemia, and the cardioprotection by diazoxide was blocked by 5-HD but not by HMR1098. 4,7 Therefore, the findings obtained from mouse hearts cannot be directly extrapolated to clinical settings.In conclusion, diazoxide-induced protective effect on the ischemia-induced contractile dysfunction of mouse heart is mediated by accelerated activation of sarcK ATP channels during ischemia, suggesting that activation of sarcK ATP channels rather than of mitoK ATP channels is important for diazoxide-induced anti-stunning effect. …”

Glimepiride, a Novel Sulfonylurea, Does Not Abolish Myocardial Protection Afforded by Either Ischemic Preconditioning or Diazoxide

“…A substantial body of evidence implicates mitochondrial K ATP channel opening as playing a central role in the acquisition of this protection. 3,19 Although it is not clearly established whether mitochondrial K ATP channel opening plays a trigger role (proximal event) or acts as a distal effector of protection, glibenclamide has been shown to attenuate this preconditioning response in animal studies (for a review, see Yellon et al 18 ). There are also data from human studies in which preconditioning has been examined with surrogate end points such as ST-segment deviation during repeated intracoronary balloon inflations that support the notion that glibenclamide blunts the preconditioning response.…”

“…To examine this hypothesis, the second aim of our study was to ascertain whether glimepiride abolished the protective role of diazoxide, a known opener of mitochondrial K ATP channels at specific doses. 7 It has been shown that diazoxide, when administered before ischemia, protects the infarcting myocardium; 19 this beneficial effect being lost in the presence of glibenclamide. 7 Our results confirm these studies with respect to glibenclamide but also demonstrate that glimepiride does not appear to abolish this protective effect; ie, the protection conferred by diazoxide is not lost even when the mitochondrial K ATP opener is given in the presence of this sulfonylurea.…”

Mitochondrial K channels in cell survival and death

“…In the absence of preconditioning, the knockout mice displayed more significant damage in response to ischemia then wild-type animals suggesting that the surface K ATP channel may play a role in cardioprotection in mice. In contrast, inhibition of the surface K ATP channels with HMR1098 does not seem to have an effect on ischemia or IPC in dogs, rats, rabbits or human myocardium [73][74][75][76], indicating a minimal role for sarcolemmal K ATP activation in cardioprotection in large animals.…”