Glucose reduces endothelin inhibition of voltage-gated potassium channels in rat arterial smooth muscle cells

Prolonged hyperglycaemia impairs vascular reactivity and inhibits voltage-activated K+ (Kv) channels. We examined acute effects of altering glucose concentration on the activity and inhibition by endothelin-1 (ET-1) of Kv currents of freshly isolated rat arterial myocytes. Peak Kv currents recorded in glucose-free solution were reversibly reduced within 200 s by increasing extra cellular glucose to 4 mM. This inhibitory effect of glucose was abolished by protein kinase C inhibitor peptide (PKC-IP), and Kv currents were further reduced in 10mM glucose. In current-clamped cells, membrane potentials were more negative in 4 than in 10 mM glucose. In 4 mM D-glucose, 10 nM ET-1 decreased peak Kv current amplitude at +60 mV from 23.5 +/- 3.3 to 12.1 +/- 3.1 pA pF(-1) (n = 6, P < 0.001) and increased the rate of inactivation, decreasing the time constant around fourfold. Inhibition by ET-1 was prevented by PKC-IP. When D-glucose was increased to 10 mM, ET-1 no longer inhibited Kv current (n = 6). Glucose metabolism was required for prevention of ET-1 inhibition of Kv currents, since fructose mimicked the effects of D-glucose, while L-glucose, sucrose or mannitol were without effect. Endothelin receptors were still functional in 10mMD-glucose, since pinacidil-activated ATP-dependent K+ (K-ATP) currents were reduced by 10 nM ET-1. This inhibition was nearly abolished by PKC-IP, indicating that endothelin receptors could still activate PKC in 10 mM D-glucose. These results indicate that changes in extracellular glucose concentration within the physiological range can reduce Kv current amplitude and can have major effects on Kv channel modulation by vasoconstrictors.