Delayed preconditioning with adenosine is mediated by opening of ATP-sensitive K⁺ channels in rabbit heart

Abstract

The adenosine agonist 2-chloro- N 6-cyclopentyladenosine (CCPA) induces delayed ischemic protection in vivo. We hypothesized that this protection is mediated by opening of ATP-sensitive K+(KATP) channels and increased synthesis of 72-kDa heat shock protein (HSP 72). Six groups ( n = 9–13 animals/group) of animals were studied: group I, control rabbits that received no treatment; group II, animals given glibenclamide (0.3 mg/kg iv) 30 min before ischemia; group III, animals given 5-hydroxydecanoate (5-HD; 5 mg/kg iv) 15 min before ischemia; group IV, rabbits treated with CCPA (0.1 mg/kg iv) 24 h before ischemia; and groups V and VI, CCPA-treated animals that received the KATP-channel blockers glibenclamide or 5-HD, respectively, 30 or 15 min before ischemia. All animals were subjected to ischemia by 30 min of coronary artery occlusion followed by 3 h of reperfusion. Risk area was delineated by injection of 10% Evans blue dye, and infarct size was determined by triphenyltetrazolium staining. Action potential duration (APD) was measured with an epicardial electrode. HSP 72 was measured by Western blotting. CCPA caused a significant reduction in infarct size [12.02 ± 1.0 vs. 40.0 ± 3.8% (%area at risk) in controls, P < 0.01] that was blocked by glibenclamide (36.2 ± 3.1%, P < 0.01) and 5-HD (35.0 ± 2.9%, P < 0.01). Glibenclamide and 5-HD did not change infarct size in control rabbits. These blockers significantly suppressed ischemia-induced APD shortening in control and CCPA-treated animals. CCPA treatment did not induce HSP 72 in hearts. These data suggest that adenosine-initiated delayed protection is mediated via opening of KATP channels but does not involve the synthesis of HSP 72.

Adenosine A 1 Receptor Activation Induces Delayed Preconditioning in Rats Mediated by Manganese Superoxide Dismutase

“…For example, we 51 and others 52 have demonstrated that A 1 R-induced delayed preconditioning is dependent on the opening of the ATP-sensitive K ϩ (K ATP ) channels during the index ischemic insult, because inhibition of K ATP channels with glibenclamide or 5-hydroxydecanoate abrogated the infarct-limiting effect of treatment with CCPA 24 hours earlier. Furthermore, on the basis of the relative selectivity of 5-hydroxydecanoate for the mitochondrial rather than the sarcolemmal K ATP channels, it has been proposed that opening of the former may mediate the delayed cardioprotective effects of A 1 R agonists.…”

Inducible Nitric Oxide Synthase Mediates Delayed Myocardial Protection Induced by Activation of Adenosine A 1 Receptors

“…Previous studies have shown that A 1 AR activation induces delayed protection in the rabbit heart. 4,6 This protection was attributed to the activation of protein kinase C (PKC) 10 and opening of the K ATP channel. 6,11 In the present study, we have shown a novel mechanism of A 1 AR-induced delayed cardioprotection in the isolated perfused mouse heart.…”

“…4,6 This protection was attributed to the activation of protein kinase C (PKC) 10 and opening of the K ATP channel. 6,11 In the present study, we have shown a novel mechanism of A 1 AR-induced delayed cardioprotection in the isolated perfused mouse heart. Stimulation of A 1 ARs with CCPA resulted in delayed cardioprotection, as indicated by a significant reduction in infarct size and improvement in postischemic ventricular function.…”

“…We originally hypothesized that CCPA-induced delayed preconditioning is mediated by opening of the K ATP channel. 6 The mediator in opening of the K ATP channel after adenosine-induced protection is not known. Because NO has been proposed to open K ATP channels, 7 we hypothesized that the A 1 AR may mediate this protective effect via an NO-sensitive mechanism.…”

Understanding myocardial ischemic preconditioning, and the implications for a role of adenosine catabolism

“…A number of studies have identified the opening of K ATP -channels as an endeffector, mediating the infarct-sparing effects of late IP (84)(85)(86)(87)(88). The opening of these channels was associated with the infarct-sparing effect of late IP but not found necessary for the protection against stunning (89).…”