Arginine vasopressin inhibits Kir6.1/SUR2B channel and constricts the mesenteric artery via V1a receptor and protein kinase C

Am J Physiol Regul Integr Comp Physiol. 2007 Jul;293(1):R191-9. doi: 10.1152/ajpregu.00047.2007. Epub 2007 Apr 11.

Abstract

Kir6.1/SUR2B channel is the major isoform of K(ATP) channels in the vascular smooth muscle. Genetic disruption of either subunit leads to dysregulation of vascular tone and regional blood flows. To test the hypothesis that the Kir6.1/SUR2B channel is a target molecule of arginine vasopressin (AVP), we performed studies on the cloned Kir6.1/SUR2B channel and cell-endogenous K(ATP) channel in rat mesenteric arteries. The Kir6.1/SUR2B channel was expressed together with V1a receptor in the HEK-293 cell line. Whole cell currents of the transfected HEK cells were activated by K(ATP) channel opener pinacidil and inhibited by K(ATP) channel inhibitor glibenclamide. AVP produced a concentration-dependent inhibition of the pinacidil-activated currents with IC(50) 2.0 nM. The current inhibition was mediated by a suppression of the open-state probability without effect on single-channel conductance. An exposure to 100 nM PMA, a potent PKC activator, inhibited the pinacidil-activated currents, and abolished the channel inhibition by AVP. Such an effect was not seen with inactive phorbol ester. A pretreatment of the cells with selective PKC blocker significantly diminished the inhibitory effect of AVP. In acutely dissociated vascular smooth myocytes, AVP strongly inhibited the cell-endogenous K(ATP) channel. In isolated mesenteric artery rings, AVP produced concentration-dependent vasoconstrictions with EC(50) 6.5 nM. At the maximum effect, pinacidil completely relaxed vasoconstriction in the continuing exposure to AVP. The magnitude of the AVP-induced vasoconstriction was significantly reduced by calphostin-C. These results therefore indicate that the Kir6.1/SUR2B channel is a target molecule of AVP, and the channel inhibition involves G(q)-coupled V1a receptor and PKC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Arginine Vasopressin / pharmacology*
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Glyburide / pharmacology
  • Humans
  • KATP Channels
  • Mesenteric Arteries / drug effects*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / physiology
  • Naphthalenes / pharmacology
  • Pinacidil / pharmacology
  • Potassium Channel Blockers*
  • Potassium Channels, Inwardly Rectifying / drug effects*
  • Protein Kinase C / antagonists & inhibitors*
  • Receptors, Vasopressin / drug effects*
  • Signal Transduction / drug effects
  • Vasoconstrictor Agents*
  • Vasodilator Agents / pharmacology

Substances

  • Enzyme Inhibitors
  • KATP Channels
  • Naphthalenes
  • Potassium Channel Blockers
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Vasopressin
  • Vasoconstrictor Agents
  • Vasodilator Agents
  • uK-ATP-1 potassium channel
  • Arginine Vasopressin
  • Pinacidil
  • Protein Kinase C
  • calphostin C
  • Glyburide