Contractile regulation of the Na+-K+-2Cl− cotransporter in vascular smooth muscle

Author:

Akar Fatma1,Jiang Gengru1,Paul Richard J.2,O'Neill W. Charles13

Affiliation:

1. Renal Division, Department of Medicine, and

2. Department of Biophysics and Molecular Physiology, University of Cincinnati, Cincinnati, Ohio 45267

3. Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322; and

Abstract

Vasoconstrictors activate the Na+-K+-2Cl cotransporter NKCC1 in rat aortic smooth muscle, but the mechanism is unknown. Efflux of86Rb+ from rat aorta in response to phenylephrine (PE) was measured in the absence and presence of bumetanide, a specific inhibitor of NKCC1. Removal of extracellular Ca2+ completely abolished the activation of NKCC1 by PE. This was not due to inhibition of Ca2+-dependent K+ channels since blocking these channels with Ba2+ in Ca2+-replete solution did not prevent activation of NKCC1 by PE. Stimulation of NKCC1 by PE was inhibited 70% by 75 μM ML-9, 97% by 2 μM wortmannin, and 70% by 2 mM 2,3-butanedione monoxime, each of which inhibited isometric force generation in aortic rings. Bumetanide-insensitive Rb+efflux, an indication of Ca2+-dependent K+channel activity, was reduced by ML-9 but not by the other inhibitors. Stretching of aortic rings on tubing to increase lumen diameter to 120% of normal almost completely blocked the stimulation of NKCC1 by PE without inhibiting the stimulation by hypertonic shrinkage. We conclude that activation of the Na+-K+-2Cl cotransporter by PE is the direct result of smooth muscle contraction through Ca2+-dependent activation of myosin light chain kinase. This indicates that the Na+-K+-2Cl cotransporter is regulated by the contractile state of vascular smooth muscle.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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