Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in isolated perfused rat hearts

Abstract

We examined influences of a blocker (glibenclamide) and an opener (nicorandil) of the ATP-sensitive potassium (KATP) channel on extracellular K concentration [( K+]e), as well as the myocardial function and metabolites during global ischemia and reperfusion in Langendorff-perfused rat heart preparation. In control hearts, [K+]e began to rise 20 s after the onset of ischemia up to an initial peak (8.3 +/- 0.3 mM) at 2.5 +/- 0.7 min, then fell to 6.0 +/- 0.8 mM after 8.2 +/- 0.7 min, and then rose progressively to 14.6 +/- 0.8 mM at the end of 30 min of ischemia. Glibenclamide (50 microM) reduced the initial peak of [K+]e to 7.2 +/- 0.3 mM (P less than 0.01), and nicorandil (200 microM) increased it to 9.4 +/- 0.6 mM (P less than 0.01). There were no significant differences in [K+]e values among all groups at the end of ischemia. During ischemia, nicorandil decreased the time to mechanical arrest from 1.9 +/- 0.1 min to 1.5 +/- 0.1 min, whereas it was increased by glibenclamide to 2.7 +/- 0.4 min. In control hearts, the time to onset of ischemic contracture was 14.7 +/- 1.8 min. Nicorandil delayed onset of contracture and glibenclamide accelerated it. Thus we have confirmed that some part of the early increase in [K+]e during ischemia is attributable to K+ efflux through the KATP channel in our model, and opening of the KATP channel may contribute to a rapid reduction of the contractility of the ischemic myocardium that subsequently protects the myocardium against further ischemic injury.

Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice

“…It has been reported that the change in [K ϩ ] o typically occurs with triphasic time courses, the initial fast rise followed by a secondary plateau phase and a third slower increase (30). Because previous studies showed that the sulfonylureas modulate the initial rate of rise of [K ϩ ] o (7,11,15,27,31), our attention has been focused primarily on the first two (initial rise and subsequent plateau) phases. In the present experiments, we continuously monitored [K ϩ ] o for a period of 10 min of ischemia and found that [K ϩ ] o increased in a biphasic manner comprising an initial rising phase and a second plateau phase.…”

“…Nevertheless, the precise mechanism underlying extracellular K ϩ accumulation is still a matter for debate. Since numerous studies demonstrated that inhibition of the ATPsensitive K ϩ (K ATP ) channels by sulfonylureas lessens the rise in [K ϩ ] o during early ischemia (7,11,15,27,31) 14), previous studies in our laboratory (23, 24) showed that neither K ATP channel openers nor metabolic inhibition abbreviates action potentials in Kir6.2 KO mouse ventricular myocytes. Therefore, Kir6.2 KO mice have no functional sarcolemmal K ATP channels in cardiac cells and are potentially useful to examine whether K ϩ efflux through K ATP channels is mainly involved in extracellular K ϩ accumulation in ischemic hearts.…”

“…Nevertheless, the precise mechanism underlying extracellular K ϩ accumulation is still a matter for debate. Since numerous studies demonstrated that inhibition of the ATPsensitive K ϩ (K ATP ) channels by sulfonylureas lessens the rise in [K ϩ ] o during early ischemia (7,11,15,27,31) (10,26,28). Thus the results obtained so far with K ATP channel openers and blockers are not conclusive.…”

Phospholipid Lysophosphatidylcholine as a Metabolic Trigger and HERG as an Ionic Pathway for Extracellular K⁺ Accumulation and “Short QT Syndrome” in Acute Myocardial Ischemia

“…7C): negative shift of activation and voltage-dependent increase with markedly more pronounced enhancement at the potentials near the resting potential of ischemic heart (145% increase at -40 mV vs. 34% increase at +20 mV). ) is gated by intracellular ATP and regulated by a variety of cellular metabolites, and it is naturally considered a sensor of the metabolic state of a myocardial cell, and activation of these channels is considered an indicator of cellular metabolic compromise [30][31][32] ] o -and APD- [7,[34][35][36][37][38]. First, the measured [ATP] i at the time of metabolic blockade of acute ischemia is still in the millimolar range which is far too high to induce massive K ATP [39,40].…”

Nicorandil Infusion Leads to Good Recovery From Ischemia of Left Ventricular Regional Work in Comparison With Nitroglycerin.

“…However, NR led to a better recovery of the RWwork from ischemia compared with NG. In isolated-perfused rat hearts, NR improved the functional and metabolic recovery after global ischemia and reperfusion, [26][27][28][29] suggesting that NR has a direct cardioprotective action and potential clinical usefulness as an adjunct therapy during reperfusion after angioplasty or thrombolysis, enabling PTCA to be performed with more safety. Because NR is not considered to develop tolerance 24,25 and has an anti-arrhythmic effect unlike nitrates because of electrocardiographic QT interval shortening, [30][31][32] it is considered to be very useful to the patients with ischemic heart disease.…”