K_ATP‐channel activation: effects on myocardial recovery from ischaemia and role in the cardioprotective response to adenosine A₁‐receptor stimulation

Abstract

1 Optimization of myocardial energy substrate metabolism improves the recovery of mechanical function of the post-ischaemic heart. This study investigated the role of K ATP -channels in the regulation of the metabolic and mechanical function of the aerobic and post-ischaemic heart by measuring the e ects of the selective K ATP -channel activator, cromakalim, and the e ects of the K ATP -channel antagonist, glibenclamide, in rat fatty acid perfused, working hearts in vitro. The role of K ATP channels in the cardioprotective actions of the adenosine A 1 -receptor agonist, N 6 -cyclohexyladenosine (CHA) was also investigated. 2 Myocardial glucose metabolism, mechanical function and e ciency were measured simultaneously in hearts perfused with modi®ed Krebs-Henseleit solution containing 2.5 mM Ca 2+ , 11 mM glucose, 1.2 mM palmitate and 100 mu l 71 insulin, and paced at 300 beats min 71 . Rates of glycolysis and glucose oxidation were measured from the quantitative production of 3 H 2 O and 14 CO 2 , respectively, from [5-3 H/ U-14 C]-glucose. 3 In hearts perfused under aerobic conditions, cromakalim (10 mM), CHA (0.5 mM) or glibenclamide (30 mM) had no e ect on mechanical function. Cromakalim did not a ect glycolysis or glucose oxidation, whereas glibenclamide signi®cantly increased rates of glycolysis and proton production. CHA signi®cantly reduced rates of glycolysis and proton production but had no e ect on glucose oxidation. Glibenclamide did not alter CHA-induced inhibition of glycolysis and proton production. 4 In hearts reperfused for 30 min following 30 min of ischaemia, left ventricular minute work (LV work) recovered to 24% of aerobic baseline values. Cromakalim (10 mM), administered 5 min before ischaemia, had no signi®cant e ect on mechanical recovery or glucose metabolism. CHA (0.5 mM) signi®cantly increased the recovery of LV work to 67% of aerobic baseline values and also signi®cantly inhibited rates of glycolysis and proton production. Glibenclamide (30 mM) signi®cantly depressed the recovery of mechanical function to 51% of aerobic baseline values and stimulated glycolysis and proton production. 5 Despite the deleterious actions of glibenclamide per se in post-ischaemic hearts, the bene®cial e ects of CHA (0.5 mM) on the recovery of mechanical function and proton production were not a ected by glibenclamide. 6 The data indicate that the cardioprotective mechanism of adenosine A 1 -receptor stimulation does not involve the activation of K ATP -channels. Furthermore, in rat fatty acid perfused, working hearts, stimulation of K ATP -channels is not cardioprotective and has no signi®cant e ects on myocardial glucose metabolism.

Role of endothelium in ischaemia‐induced myocardial dysfunction of isolated working hearts: cardioprotection by activation of adenosine A2A receptors

“…Pacing could not resolve this question as there was no recovery of AO in control paced hearts. Most studies that have demonstrated a cardioprotective effect of A 1 receptor activation have applied the agonist prior to ischaemia (Mentzer et al ., 1993; Ford, Lopaschuk, Schulz & Clanahan, 1998), rather than during ischaemia and reperfusion as in the present study.…”

Effects of the cardioselective K ATP channel blocker HMR 1098 on cardiac function in isolated perfused working rat hearts and in anesthetized rats during ischemia and reperfusion

“…A similar cardiodepressant effect of the sulfonylurea glibenclamide was recently reported by Ford et al (1998), who subjected isolated working rat hearts to 30 min of global ischemia followed by 30 min of reperfusion. In the presence of 30 µmol/l glibenclamide, left ventricular work was markedly depressed during reperfusion as compared to hearts in the absence of glibenclamide.…”

“…Indeed, animal models exist in which cardiodepressant effects of sulfonylureas have been demonstrated. For example, in isolated working rat hearts subjected to global ischemia followed by reperfusion, the ventricular work was significantly depressed by glibenclamide (Ferdinandy et al 1995;Ford et al 1998).…”

Adenosine enhances cytosolic phosphorylation potential and ventricular contractility in stunned guinea pig heart: receptor-mediated and metabolic protection

“…Also Yao and Gross (44) demonstrated in in vivo dog hearts that glibenclamide abolished the protection against stunning afforded by the A 1 agonist CCPA. In contrast, Ford et al (10) found no inhibition of functional protection by glibenclamide in working rat hearts. However, the protocol of Ford et al and the Yao and Gross stunning protocol differ from ours and in crucial aspects.…”