Opening of Potassium Channels

Abstract

Background-The tolerance of hibernating mammals to cold hypoxia is related to a factor similar to agonists of ␦-opioid receptors. This study was designed to assess whether activation of these receptors could reproduce the protection conferred by ischemic preconditioning and whether such cardioprotection was similarly mediated by an opening of ATP-sensitive potassium (K ATP ) channels. Methods and Results-Thirty-two isolated rat hearts were arrested with and stored in Celsior at 4°C for 5 hours before being reperfused for 2 hours. They were divided into 4 equal groups. Group 1 hearts served as controls. In group 2, ischemic preconditioning was elicited by two 5-minute global ischemia periods interspersed with 5 minutes of reperfusion before arrest. In group 3, hearts were pharmacologically preconditioned with a 15-minute infusion of the ␦-opioid receptor agonist D-Ala2-D-Leu5-enkephalin (DADLE; 200 mol/L). In group 4, the protocol was similar to group 3 except that infusion of DADLE was preceded by infusion of the K ATP blocker glibenclamide (50 mol/L). The salutary effects of both forms of preconditioning were primarily manifest as a better preservation of diastolic function, a reduced myocardial edema, and reduced creatine kinase leakage. This protection was abolished by administration of glibenclamide before DADLE. Conclusions-These data suggest that activation of ␦-opioid receptors improves recovery of cold-stored hearts to a similar extent as ischemic preconditioning, most likely through an opening of K ATP channels. This provides a rationale for improving the preservation of hearts for transplantation by pharmacologically duplicating the common pathway to natural hibernation and preconditioning. (Circulation. 1999;99:3079-3085.)

Tandem Function of Nucleotide Binding Domains Confers Competence to Sulfonylurea Receptor in Gating ATP-sensitive K+ Channels

“…The resulting alteration in channel activity is proposed to promote survival at low temperature by membrane potential clamping, as well as maintenance of ionic and energetic homeostasis (49). Moreover, in mammals, a cardioprotective effect of K ATP channels is also present at low temperature, and this effect has been exploited in cardioplegia procedures (50). Thus, the results of the current study provide a working model of K ATP channel function and point to potential avenues in addressing the biology of cold tolerance (51).…”

“…On average, in inside-out patches (Fig. 2B, upper panel) ATPinduced channel inhibition was markedly reduced from an initial IC 50 (Fig. 2B, lower panel), a distinct patch condition, the sensitivity of K ATP channels toward ATP was reduced from an initial IC 50 of 270 Ϯ 21 M (n ϭ 6 -14) to 1.6 Ϯ 0.2 mM (n ϭ 2-7) after cooling.…”

Myocardial protection by anesthetic agents against ischemia-reperfusion injury: An update for anesthesiologists

“…Morphine, pentazocine and buprenorphine improved mechanical function after global total ischemia for two hours at 34°C. 65,68 Opioids also elicited a protective effect in heart preservation at 4 or 10°C for four to18 hr; [68][69][70] this might be an indication of the usefulness of opioids in heart transplantation. 6 6.…”

“…The beneficial effects were eliminated by a G i protein inhibitor, 81 a PKC inhibitor, 62,67,85,86 and a selective mitochondrial K ATP channel blocker. 63,66,70,76,82,83,85,86 The effect of "classic" or "early" ischemic preconditioning is transient and lost within 0.5-2 hr after brief ischemic episodes, but the protection exhibits a biphasic time course and returns after 24 hr. 20,22 This late protection is called "late", "delayed" or "second window" preconditioning.…”

Effect of a δ Receptor Agonist on Duration of Survival during Hemorrhagic Shock

“…1,2,5,[17][18][19] Because of these responses, DADLE is often referred to as the hibernation induction trigger (HIT), and is thought by some investigators to provide the theoretical link between cardioprotective mechanism of IP and animal hibernation. [20][21][22][23][24] When infused systemically in whole animals, DADLE produces a 30-40% reduction in the metabolic rate, with very little impact on arterial pressure. 25 This constellation of actions makes this particular d receptor agonist an excellent candidate for use in the treatment of shock states.…”