title: Downregulation of Kv7.4 channel activity in primary and secondary hypertension.
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.
  
  
  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.
authors: Division of Biomedical Sciences, St. George's, University of London, United Kingdom.
authors: Thomas A
authors: TA
authors: Jepps
authors: Preet S
authors: PS
authors: Chadha
authors: Alison J
authors: AJ
authors: Davis
authors: Maksym I
authors: MI
authors: Harhun
authors: Gillian W
authors: GW
authors: Cockerill
authors: Søren P
authors: SP
authors: Olesen
authors: Rie S
authors: RS
authors: Hansen
authors: Iain A
authors: IA
authors: Greenwood
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008638:Mesenteric Arteries / Q000502:physiology; D051379:Mice; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C424388:BMS204352; D002219:Carbamates; D007211:Indoles; D051656:KCNQ Potassium Channels; C492167:Kcnq4 protein, mouse; C492166:Kcnq4 protein, rat; D010655:Phenylenediamines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C101866:ezogabine