Coordinate Interaction Between ATP-Sensitive K ⁺ Channel and Na ⁺ ,K ⁺ -ATPase Modulates Ischemic Preconditioning

Abstract

Background-We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC).Because ATP-sensitive K ϩ (K ATP ) channels are involved in IPC, we studied whether Na ϩ ,K ϩ -ATPase and K ATP channels functionally interact, thereby modulating IPC. Methods and Results-Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2Ϯ2.8% in control and 39.8Ϯ5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a K ATP channel opener, reduced IS to 11.8Ϯ1.8% and 13.4Ϯ2.6% (PϽ0.05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5Ϯ3.3%), whereas it did not change that induced by cromakalim (18.8Ϯ3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of K ATP channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration. Conclusions-The IS-limiting effect of IPC is modulated by an interaction between K ATP channels and Na ϩ ,K ϩ -ATPase through subsarcolemmal ATP. (Circulation. 1998;98:2905-2910.)

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

“…Numerous studies have demonstrated a role for Na/KATPase in the heart's response to ischemia reperfusion (39). Notably, a functional link between Na/K-ATPase and K ATP has also been described (27). Haruna et al (27) demonstrated that a coordinate interaction between the K ATP channel and Na/KATPase modulates ischemic preconditioning.…”

“…Proteins-In heart and other tissues, K ATP channel function has been tightly linked with the activity of the Na/K-ATPase (27,28). Notably, work from our group and others has demonstrated direct high affinity interaction of ankyrin with Na/KATPase (ankyrin-B in heart) and loss of membrane Na/K-ATPase in ankyrin-deficient cells (9, 29 -31).…”

Gentamicin-induced preconditioning of proximal tubular LLC-PK1 cells stimulates nitric oxide production but not the synthesis of heat shock protein

“…The mechanisms involved in preconditioning are not fully understood, but may depend on the release of endog-Preconditioning with gentamicin of LLC-PK1 cells www.bjournal.com.br enous protective mediators such as adenosine (13), prostacyclin (14), bradykinin (15), nitric oxide (NO) (9), opening of K ATP channels (16), endothelin 1 decrease (17), and heat shock protein (HSP) synthesis (18). The protective effect of the initial preconditioning stress may involve the ability of tissue to induce HSP synthesis (19,20) and to increase NO production (21).…”

Sarcolemmal and mitochondrial KATP channels and myocardial ischemic preconditioning

“…However, digoxin did not alter the protective effects of the K ATP opener, cromakalim, since K ATP channel openers would be expected to act directly on the channels, and thus, have effects independent of ATP concentrations. Furthermore, diazoxide, a selective mitoK ATP channel opener, failed to reduce infarct size when administered at a similar or 10-fold higher dose than that needed for cromakalim to produce its infarct-limiting effects [23]. This is of special note, given that Garlid et al [24] demonstrated that cromakalim and diazoxide display a similar degree of potency for opening mitoK ATP in reconstituted mitochondria and elicited a similar degree of cardioprotection following ischemia-reperfusion in the isolated rat heart.…”

“…Haruna et al [23] recently reported that the infarct limiting effect of IPC may be modulated via an interaction between Na + -K + ATPase and sarcK ATP channels. In this study, the infarct-limiting effects of IPC in anesthetized rabbits were abolished by digoxin, an inhibitor of Na + -K + ATPase [23]. By inhibiting Na + -K + ATPase, digoxin would raise the amount of subsarcolemmal ATP, preventing the opening of the sarcK ATP channel during IPC.…”