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Calcium Modulation of Vascular Smooth Muscle ATP-Sensitive K + Channels

2000; Lippincott Williams & Wilkins; Volume: 87; Issue: 11 Linguagem: Inglês

10.1161/01.res.87.11.1019

1524-4571

Andrew J. Wilson, Rita I. Jabr, Lucie H. Clapp,

Cardiac electrophysiology and arrhythmias

Abstract —ATP-sensitive K + (K ATP ) channels are broadly distributed in the vasculature and regulate arterial tone. These channels are inhibited by intracellular ATP ([ATP] i ) and vasoconstrictor agents and can be activated by vasodilators. It is widely assumed that K ATP channels are insensitive to Ca 2+ , although regulation has not been examined in the intact cell where cytosolic regulatory processes may be important. Thus we investigated the effects of Ca 2+ on whole-cell K ATP current in rat aortic smooth muscle cells recorded in a physiological [ATP] i and K + gradient. Under control recording conditions, cells had a resting potential of ≈−40 mV when bathed in 1.8 mmol/L Ca 2+ . The K ATP channel inhibitor glibenclamide caused membrane depolarization (9 mV) and inhibited a small, time-independent background current. Reducing [ATP] i from 3 to 0.1 mmol/L hyperpolarized cells to ≈−60 mV and increased glibenclamide-sensitive current by 2- to 4-fold. Similar effects were observed when Ca 2+ levels were decreased either externally or internally by increasing EGTA from 1 to 10 mmol/L. Dialysis with solutions containing different free [Ca 2+ ] i showed that K ATP current was maximally activated at 10 nmol/L [Ca 2+ ] i and almost totally inhibited at 300 nmol/L. Moreover, under control conditions, when rat aortic smooth muscle cells were dialyzed with either cyclosporin A, FK-506, or calcineurin autoinhibitory peptide (structurally unrelated inhibitors of Ca 2+ -dependent protein phosphatase, type 2B), glibenclamide-sensitive currents were large and the resting potential was hyperpolarized by ≈20 to 25 mV. We report for the first time that K ATP channels can be modulated by Ca 2+ at physiological [ATP] i and conclude that modulation occurs via protein phosphatase type 2B.