Oral nicorandil recaptures the waned protection from preconditioning in vivo

Abstract

1 Protection from preconditioning (PC) wanes and is eventually lost when multiple bouts of short ischemia or a prolonged reperfusion interval precedes the following sustained ischemia. The activation of mitochondrial K ATP channels plays a pivotal role in the intracellular signaling of PC. We tested whether the K ATP channel opener nicorandil (nic) preserves the given protection from PC in conditions where this benefit decays and is lost. 2 Eight groups of rabbits were divided into two equal series of experiments, one without nic (placebo) and one with nic treatment. Nic was given orally for 5 consecutive days in a dose of 5 mg kg À1 d À1 . In a second step, four additional groups were treated with nic plus the K ATP channel blocker 5HD and 1 additional control group with nitroglycerin only. All the animals were anesthetized and then subjected to 30 min of myocardial ischemia and 2 h of reperfusion with one of the following interventions before the sustained ischemia: Control groups to no intervention; 3PC groups to three cycles of 5-min ischemia-10-min reperfusion; 8PC groups to eight cycles of 5-min ischemia -10-min reperfusion; and 3PC90 groups to the same interventions as the 3PC groups but with a prolonged (90 min) intervening reperfusion interval before the sustained ischemia. The infarcted and the risk areas were expressed in percent. 3 There was no significant change in infarct size between the placebo, the nic and the 5HD-nic in the control groups (41.574.7, 43.977.1 and 48.776.4%) and 3PC groups (10.373.4, 12.273.9 and 12.674.5%). However, there was a significant decrease after nic treatment in groups 8PC (47.778.8% vs 13.072.6%, Po0.01) and 3PC90 (37.376.0% vs 14.272.4%, Po0.01), which was abrogated (38.274.7 and 42.774.4%, respectively, for 8PC and 3PC90 groups). Nitroglycerin had no effect on infarct size (39.173.1%, P ¼ NS vs other controls). 4 Oral treatment with nic recaptures the waned protection of PC, both after repetitive bouts of short ischemia or after a prolonged reperfusion interval, preserving the initially obtained benefit. Nic by itself is insufficient to initiate PC in vivo.

What is Wrong With Cardiac Conditioning? We May be Shooting at Moving Targets

“…Nicorandil is an agent that activates mitochondrial adenosine triphosphate-dependent potassium channels. 89,90 There have been relatively few animal studies demonstrating a direct anti-infarct effect of this agent. Nicorandil showed no effect against infarction in the J-WIND study, while ANP did.…”

Remote Postconditioning is More Potent than Classic Postconditioning in Reducing the Infarct Size in Anesthetized Rabbits

“…The areas of infarction and of myocardial tissue at risk of infarction were automatically transformed to volumes by multiplying by the slice thickness (3 mm). Infarct and risk area volumes were expressed as cm 3 and the percent of infarct to risk area (I/R) calculated as previously described [5].…”

“…More recently, another therapeutic intervention, called ischemic postconditioning, consisted of very short-lived episodes of ischemia/reperfusion applied immediately after the end of sustained ischemia has been described as an intervention that diminishes the reperfusion injury [4]. Both pre-and postconditioning reduce the myocardial infarction by eliminating the detrimental effect of reperfusion injury and novel therapeutic strategies as pharmacological mimetics or alternative strategies of "conditioning" are used as potential therapeutic interventions [5][6][7][8].…”

The Application of Atp-Sensitive Potassium Channels^ Opener-Nicorandil in Treatment of Coronary Heart Disease

“…Защитный эффект никорандила, наблюдаемый у больных с ИМ, объ-ясняет ся улучшением коронарной перфузии в пе-риинфарктной зоне за счет вазодилатации, а так-же стимулирования прекондиционирования. Кар-диопротективное действие прекондиционирования выражается в уменьшении размеров инфаркта, улучшении систолической функции левого желу-дочка, снижении частоты жизнеугрожающих арит-мий [33,[35][36][37][38]. Кроме того, никорандил положи-тельно влияет на процессы постинфарктного ре-моделирования миокарда [39].…”