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

Abstract

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 extracellular 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 10 mm 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 10 mm d-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.

Selective Down-regulation of KV2.1 Function Contributes to Enhanced Arterial Tone during Diabetes

“…In addition to transcriptional suppression of K V 2.1 subunit expression, post-translational modification of this (and other K V ) subunit may also contribute to a reduction in I Kv during diabetes (11)(12)(13)(45)(46)(47). Hence, multiple mechanisms may potentially synergize and contribute to impaired K V function, and vascular complications during diabetes.…”

“…Previous reports have shown that in vitro, short term exposure of coronary, cerebral, and mesenteric arteries to extracellular glucose concentrations that resemble diabetic hyperglycemia (e.g. 20 mM) inhibit K V and BK Ca channel activity in VSMCs (11)(12)(13)(14)(15). Thus, inhibition of these channels may contribute to enhanced arterial tone and vascular complications during diabetes.…”

Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia

“…7 An increase in extracellular glucose also impacts the function of other ion channels in arterial myocytes. Indeed, acute and chronic exposure to HG has been shown to suppress the expression and/or activity of K C channels in coronary, 9 mesenteric, 10 and cerebral arterial myocytes. ] i in arterial myocytes or vasoconstriction in arteries from S1928A mice.…”

Insulin-like growth factor-I inhibits rat arterial KATP channels through pI 3-kinase

“…We have shown that activation of PKC is involved in the inhibition of arterial K ATP channels by angiotensin II (Ang II) and endothelin-1 (ET-1) [11,17]. We therefore investigated the effects of U 73122, which gives half-inhibition of PLC-mediated Ca 2+ responses in rat portal vein cells at 0.25 M [18].…”