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

TY - JOUR

T1 - Downregulation of Kv7.4 channel activity in primary and secondary hypertension

AU - Jepps, Thomas Andrew

AU - Chadha, Preet S

AU - Davis, Alison J

AU - Harhun, Maksym I

AU - Cockerill, Gillian W

AU - Olesen, Søren Peter

AU - Hansen, Rie S

AU - Greenwood, Iain A

PY - 2011/8/2

Y1 - 2011/8/2

N2 - 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.

AB - 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.

KW - Angiotensin II

KW - Animals

KW - Aorta, Thoracic

KW - Blood Pressure

KW - Carbamates

KW - Down-Regulation

KW - Hypertension

KW - Indoles

KW - KCNQ Potassium Channels

KW - Male

KW - Membrane Potentials

KW - Mesenteric Arteries

KW - Mice

KW - Phenylenediamines

KW - Rats

KW - Rats, Inbred SHR

KW - Rats, Wistar

KW - Vasoconstrictor Agents

U2 - 10.1161/CIRCULATIONAHA.111.032136

DO - 10.1161/CIRCULATIONAHA.111.032136

M3 - Journal article

C2 - 21747056

SN - 0009-7322

VL - 124

SP - 602

EP - 611

JO - Circulation

JF - Circulation

IS - 5

ER -