Myocardial KATP channels are critical to Ca2+ homeostasis in the metabolically stressed heart in vivo.

MYOCARDIAL ATP-SENSITIVE POTASSIUM (KATP) channels appear to play central roles in the adaptation of the heart to both physiological and pathological metabolic stress (1, 3, 5, 7, 8, 14, 16, 21). In the heart, KATP channels are thought to act as metabolic sensors that respond (by opening) when cytosolic [ATP] falls and cellular energy status is diminished (1, 4, 13, 14). There are two types of KATP channels in the heart: the sarcolemmal KATP (sarcKATP) channel, minimally composed of four Kir6.2 (pore forming) and four modulatory SUR2A subunits (1, 9, 10, 12), and a putative mitochondrial KATP channel (5, 6, 16, 17). The protein composition of the mitochondrial KATP channel has not been definitively established. Myocardial KATP channels have been intensively studied, and much work has been devoted to elucidating the respective physiological roles of the sarcolemmal and mitochondrial forms of the KATP channel (sarcKATP and mitoKATP, respectively). For example, in many types of acute cardiac preconditioning, it has been shown that putative mitoKATP channel blockade abolishes the ensuing cardioprotection against severe metabolic challenge, whereas blockade of sarcKATP channels does not (5, 6, 16, 17). On the other hand, sarcKATP channels appear to be important in initiating the preconditioning response and in providing an critical adaptive mechanism to cope with acute metabolic stress (2, 3, 8, 17, 20, 21). For these and many other reasons, considerable effort has been devoted to better understanding the significance of each of these cardiac KATP channel subtypes to the physiology of the heart. Early studies of cardiac sarcKATP channels demonstrated that metabolic stress was capable of eliciting a profound hyperpolarizing K current (9, 14, 15). These observations gave rise to speculation that sarcKATP channel-mediated hyperpolarization serves to protect the intact heart with protection against Ca overload in the face of severe metabolic stress. A number of subsequent studies on isolated cardiac cells or cell lines derived from the heart have been conducted, and the results are consistent with this hypothesis (19, 21). In this issue of American Journal of Physiology-Heart and Circulatory Physiology, Gumina et al. (7) utilized manganese enhanced cardiac magnetic resonance imaging (MECMRI) to assess the effects of increased metabolic demand on myocardial Ca accumulation in intact wild-type and Kir6.2 knockout mice. A key finding of this study was that in the face of metabolic stress, myocardial Ca accumulation was markedly pronounced and myocardial function was impaired in hearts deficient in functional sarcKATP channels. Whereas these findings are arguably predictable from earlier work on isolated cardiac cells (19, 21), the work of Gumina et al. (7) is important because it is the first to provide in vivo evidence for a central role of sarcKATP channels in defending the myocardium against Ca overload and ensuing ventricular dysfunction. In this respect, it lends credence to the earlier and widely accepted interpretations of work performed on reduced myocardial preparations. Another important observation made by Gumina et al. (7) is that relative to hearts from males, the effect of sarcKATP channel deficiency on myocardial Ca accumulation and ventricular function was more profound in hearts from female mice. There is evidence that the myocardial KATP channel subunit expression is strongly influenced by estrogen (19) and that the increased resistance of the female heart to ischemiareperfusion injury is attributable to the greater protein expression of Kir6.2 and SUR2A and an increased reliance on sarcKATP channel function (2, 3, 11, 18, 19). The work of Gumina et al. (7) provides direct support for the idea that the enhanced ability of the female heart to defend against myocardial Ca accumulation in the face of metabolic stress is due, at least in part, to a greater reliance on sarcKATP channel function. Clearly, much work remains to be done to clarify the precise role of sarcKATP channels in the myocardial response to metabolic stress. However, the current work of Gumina et al. (7) provides some assurance that our speculations about the role of sarcKATP channels in myocardial Ca regulation, derived primarily from studies of reduced myocardial preparations, are also applicable to the heart in vivo.