To examine the role of sarcolemmal K-ATP channels in cardiac function, we g
enerated transgenic mice expressing GFP-tagged Kir6.2 subunits with reduced
ATP sensitivity under control of the cardiac alpha -myosin heavy chain pro
moter. Four founder mice were isolated, and both founders and progeny were
all apparently normal and fertile. Electrocardiograms from conscious animal
s also appeared normal, although mean 24-hour heart rate was approximately
10% lower in transgenic animals compared with littermate controls. In excis
ed membrane patches, K-ATP channels were very insensitive to inhibitory ATP
: mean K-1/2 ([ATP] causing half-maximal inhibition) was 2.7 mmol/L in high
-expressing line 4 myocytes, compared with 51 mu mol/L in littermate contro
l myocytes. Counterintuitively, K-ATP channel density was approximate to4-f
old lower in transgenic membrane patches than in control. This reduction of
total K-ATP conductance was confirmed in whole-cell voltage-clamp conditio
ns, in which K-ATP was activated by metabolic inhibition. K-ATP conductance
was not obvious after break-in of either control or transgenic myocytes, a
nd there was no action potential shortening in transgenic myocytes. In mark
ed contrast to the effects of expression of similar transgenes in pancreati
c beta -cells, these experiments demonstrate a profound tolerance for reduc
ed ATP sensitivity of cardiac K-ATP channels and highlight differential eff
ects of channel activity in the electrical activity of the 2 tissues.