Downregulation of Kv7.4 channel activity in primary and secondary hypertension

Circulation. 2011 Aug 2;124(5):602-11. doi: 10.1161/CIRCULATIONAHA.111.032136. Epub 2011 Jul 11.

Abstract

Background: Voltage-gated potassium (K(+)) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals.

Methods and results: Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352=S-1>retigabine. We also tested these agents in the coronary circulation using the Langendorff heart preparation. BMS-204352 and S-1 dose dependently increased coronary perfusion at concentrations between 0.1 and 10 μmol/L, whereas retigabine was effective at 1 to 10 μmol/L. In addition, S-1 increased K(+) currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K(+) currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (≈3.7 fold) in SHRs aorta. Kv7.4 protein levels were ≈50% lower in aortas and mesenteric arteries from spontaneously hypertensive rats compared with normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 were observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared with normotensive controls.

Conclusions: In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Aorta, Thoracic / physiology
  • Blood Pressure / physiology
  • Carbamates / pharmacology
  • Down-Regulation / physiology
  • Hypertension / chemically induced
  • Hypertension / physiopathology*
  • In Vitro Techniques
  • Indoles / pharmacology
  • KCNQ Potassium Channels / agonists
  • KCNQ Potassium Channels / physiology*
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mesenteric Arteries / physiology
  • Mice
  • Phenylenediamines / pharmacology
  • Rats
  • Rats, Inbred SHR
  • Rats, Wistar
  • Vasoconstrictor Agents / pharmacology

Substances

  • BMS204352
  • Carbamates
  • Indoles
  • KCNQ Potassium Channels
  • Kcnq4 protein, mouse
  • Kcnq4 protein, rat
  • Phenylenediamines
  • Vasoconstrictor Agents
  • Angiotensin II
  • ezogabine