Reduced Ca -dependent activation of large-conductance Ca -activated K channels from arteries of Type 2 diabetic Zucker diabetic fatty rats

Burnham, Matthew P., Ian T. Johnson, and Arthur H. Weston. Reduced Ca -dependent activation of large-conductance Ca -activated K channels from arteries of Type 2 diabetic Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol 290: H1520–H1527, 2006. First published November 4, 2005; doi:10.1152/ajpheart.00827.2005.—Although it is well established that diabetes impairs endotheliumdependent vasodilation, including those pathways involving vascular myocyte large-conductance Ca -activated K channels (BKCa), little is known about the effects of diabetes on BKCa activation as an intrinsic response to contractile stimulation. We have investigated this mechanism in a model of Type 2 diabetes, the male Zucker diabetic fatty (ZDF) rat. BKCa function in prediabetic (5–7 wk) and diabetic (17–20 wk) ZDF and lean control animals was assessed in whole arteries using myograph and electrophysiology techniques and in freshly dissociated myocytes by patch clamping. Log EC25 values for phenylephrine concentration-tension curves were shifted significantly to the left by blockade of BKCa with iberiotoxin (IBTX) in arteries from nonand prediabetic animals but not from diabetic animals. Smooth muscle hyperpolarizations of arteries evoked by the BKCa opener NS-1619 were significantly reduced in the diabetic group. Voltage-clamp recordings indicated that IBTX-sensitive currents were not enhanced to the extent observed in nondiabetic controls by increasing the Ca concentration in the pipette solution or the application of NS-1619 in myocytes from diabetic animals. An alteration in the expression of BKCa 1 subunits was not evident at either the mRNA or protein level in arteries from diabetic animals. Collectively, these results suggest that myocyte BKCa of diabetic animals does not significantly oppose vasoconstriction, unlike that of prediabetic and control animals. This altered function was related to a reduced Ca -dependent activation of the channel not involving 1 subunits.