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Reduced Ca²⁺-dependent activation of large-conductance Ca²⁺-activated K⁺ channels from arteries of Type 2 diabetic Zucker diabetic fatty rats

Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom

Submitted 3 August 2005 ; accepted in final form 3 November 2005

Although it is well established that diabetes impairs endothelium-dependent vasodilation, including those pathways involving vascular myocyte large-conductance Ca²⁺-activated K⁺ channels (BK_Ca), little is known about the effects of diabetes on BK_Ca 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. BK_Ca 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 BK_Ca with iberiotoxin (IBTX) in arteries from non- and prediabetic animals but not from diabetic animals. Smooth muscle hyperpolarizations of arteries evoked by the BK_Ca 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 Ca²⁺ concentration in the pipette solution or the application of NS-1619 in myocytes from diabetic animals. An alteration in the expression of BK_{Ca 1} subunits was not evident at either the mRNA or protein level in arteries from diabetic animals. Collectively, these results suggest that myocyte BK_Ca of diabetic animals does not significantly oppose vasoconstriction, unlike that of prediabetic and control animals. This altered function was related to a reduced Ca²⁺-dependent activation of the channel not involving ₁ subunits.

diabetes; vascular myocyte; iberiotoxin; N-nitro-L-arginine

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