Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest Francis G Spinale, MD, PhD The Annals.

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Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest Francis G Spinale, MD, PhD The Annals of Thoracic Surgery Volume 68, Issue 5, Pages 1934-1941 (November 1999) DOI: 10.1016/S0003-4975(99)01034-6

Fig 1 Intracellular Ca2+ concentration was measured in the same myocyte during cardioplegic arrest (4°C Ringer’s solution containing 24 mEq/L potassium) and with reperfusion (n = 30), as well as in normothermic control myocytes (n = 30). A significant increase in intracellular Ca2+ was observed during the hyperkalemic cardioplegic arrest interval, which persisted during the period of reperfusion and rewarming. Thus, hyperkalemic cardioplegic arrest caused a prolonged elevation in myocyte intracellular Ca2+ and is associated with myocyte contractile dysfunction with reperfusion and rewarming. See text for further details. (Reproduced from Dorman BH, Hebbar L, Hinton RB, Roy RC, Spinale FG. Preservation of myocyte contractile function after hypothermic cardioplegic arrest by activation of ATP-sensitive potassium channels. Circulation 1997;96:2376–84, [17] with permission from the American Heart Association.) The Annals of Thoracic Surgery 1999 68, 1934-1941DOI: (10.1016/S0003-4975(99)01034-6)

Fig 2 A hypothetical model of the mechanism of myocyte preconditioning in the setting of cardioplegic arrest. Adenosine augmentation or activation of the ATP-sensitive potassium channel provided similar protective effects on myocyte contractile processes with cardioplegic arrest and rewarming. Therefore, adenosine augmentation or activation of the ATP-sensitive potassium channel may operate through a common transduction pathway. The adenosine A1 receptor is coupled to an inhibitory guanine nucleotide binding protein complex (Gi) [34]. Increased adenosine levels activate the adenosine A1 receptor, with subsequent activation of phospholipase C (PLC) [48, 64, 65]. In turn, phospholipase C increases the activity of protein kinase C (PKC) [65], which activates the ATP-sensitive potassium channel [53]. ATP-sensitive potassium channels can be directly activated by potassium channel openers (PCOs). Thus, ATP-sensitive potassium channel activation either by adenosine A1 receptor stimulation or by a PCO maintains a hyperpolarized membrane potential [42, 66] and may therefore play a role in mediating the protective effects of preconditioning on myocyte contractile processes with cardioplegic arrest and rewarming. (Reprinted from Handy JR, Dorman BH, Cavallo MJ, et al. Direct effects of oxygenated crystalloid or blood cardioplegia on isolated myocyte contractile function. J Thorac Cardiovasc Surg 1996;112:1064–72, with the permission of the publisher.) The Annals of Thoracic Surgery 1999 68, 1934-1941DOI: (10.1016/S0003-4975(99)01034-6)