title: Endothelium-dependent relaxations in the aorta from K(2p)6.1 knockout mice.
abstract: K2P6.1 or TWIK-2, a two-pore domain K channel, is an important regulator of cardiovascular function. K2P6.1 is highly expressed in vascular smooth muscle and endothelium. Mice (8-12 wk) lacking functional K2P6.1 (K2P6.1(-/-)) are hypertensive and have enhanced vascular contractility. It is not known whether the lack of functional K2P6.1 in endothelium has a role in the vascular dysfunction in K2P6.1(-/-) mice. We tested the hypothesis: K2P6.1(-/-) mice have impaired endothelium-dependent relaxations. K2P6.1(-/-) mice were ∼35 mmHg more hypertensive than WT mice at both 8-12 wk (young adult) and 20-24 wk (mature mice, P < 0.01; n = 8-10). Endothelium-dependent relaxations of the thoracic aorta were evaluated by isometric myography after contraction with phenylephrine (10(-6) M). Maximal ACh-dependent relaxations were increased from 65 ± 1% to 73 ± 1% in the aorta from young adult (P < 0.01; n = 6) and from 45 ± 1% to 74 ± 1% in the aorta from mature (P < 0.001; n = 5) K2P6.1(-/-) mice compared with K2P6.1(+/+) littermates. However, in the aorta from young adult and mature K2P6.1(+/+) mice, 10(-5) M indomethacin, a cyclooxygenase inhibitor, increased maximal ACh relaxations to knockout levels. Enhanced relaxation was also seen with ATP, a P2Y purinergic agonist, and A23187, a nonreceptor-based agonist in mature K2P6.1(-/-) mice. Mature adult aorta from K2P6.1(-/-) showed an attenuated ACh-mediated contraction in the presence of nitro-l-arginine methyl ester (l-NAME) and without precontraction of 0.97 mN vs. 7.5 mN in K2P6.1(-/-) and K2P6.1(+/+) (P < 0.001; n = 5). In summary, K2P6.1(-/-) mice, which are hypertensive, have enhanced endothelium-dependent relaxations in the aorta due to the suppression of an indomethacin-sensitive constrictor component.
authors: Department of Anesthesiology, Baylor College of Medicine, Houston, TX 77030, USA. eelloyd@bcm.edu
authors: Eric E
authors: EE
authors: Lloyd
authors: Lavannya M
authors: LM
authors: Pandit
authors: Randy F
authors: RF
authors: Crossland
authors: Sean P
authors: SP
authors: Marrelli
authors: Robert M
authors: RM
authors: Bryan
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology*; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: C492208:Kcnk6 protein, mouse; D024683:Potassium Channels, Tandem Pore Domain; D010656:Phenylephrine; D000001:Calcimycin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin
keywords: K2p6.1; endothelial dysfunction; endothelium-dependent relaxation; hypertension; two-pore domain potassium channels
references: Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1652-61
references: 22539597
references: Hypertension. 2001 Apr;37(4):1108-13
references: 11304511
references: Circulation. 1990 Feb;81(2):491-7
references: 2105174
references: Hypertension. 1997 Mar;29(3):736-43
references: 9052889
references: Curr Opin Nephrol Hypertens. 2001 Mar;10(2):257-61
references: 11224702
references: Hypertension. 1994 Oct;24(4):499-505
references: 8088918
references: Stroke. 2000 Mar;31(3):760-4; discussion 765
references: 10700516
references: Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):42-8
references: 11788459
references: Hypertension. 1997 Jan;29(1 Pt 2):435-41
references: 9039139
references: Hypertension. 2001 Jun;37(6):1450-7
references: 11408394
references: Clin Exp Pharmacol Physiol. 1994 Nov;21(11):857-63
references: 7882576
references: Hypertension. 1992 May;19(5):442-5
references: 1568762
references: Drugs. 1997;53 Suppl 1:30-41
references: 9034753
references: J Pharmacol Exp Ther. 2010 Aug;334(2):373-80
references: 20444882
references: Arterioscler Thromb Vasc Biol. 1999 Nov;19(11):2762-8
references: 10559023
references: Hypertension. 1986 Apr;8(4):344-8
references: 2870025
references: Curr Hypertens Rep. 2010 Aug;12(4):267-75
references: 20532699
references: Br J Pharmacol. 2006 Jan;147(1):45-54
references: 16258525
references: J Physiol. 2011 Jul 1;589(Pt 13):3231-46
references: 21486782
references: Gen Pharmacol. 1998 Jan;30(1):79-83
references: 9457485
references: Int J Hypertens. 2011;2011:281240
references: 21915370
references: Hypertension. 2001 Feb;37(2 Pt 2):444-8
references: 11230316
references: Eur Biophys J. 2009 Mar;38(3):305-18
references: 18449536
references: Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2434-40
references: 16040712
references: Hypertension. 2011 Oct;58(4):672-8
references: 21876070
references: Hypertension. 1996 Jul;28(1):58-63
references: 8675265
references: Circ Res. 2003 Jul 25;93(2):96-105
references: 12881475
references: Hypertension. 1986 Jun;8(6 Pt 2):II61-6
references: 3087875
references: Life Sci. 2006 Jul 10;79(7):646-53
references: 16546219
references: Genome Res. 1998 Jul;8(7):711-23
references: 9685318
references: Am J Physiol. 1998 Feb;274(2):R375-82
references: 9486294
references: N Engl J Med. 2010 Feb 18;362(7):590-9
references: 20089957
references: N Engl J Med. 2002 Jun 20;346(25):1954-62
references: 12075056
references: Br J Pharmacol. 2004 May;142(1):192-202
references: 15066906
references: Circ Res. 2007 Jul 20;101(2):176-84
references: 17556656
references: J Am Coll Cardiol. 2001 Mar 1;37(3):863-70
references: 11693763
references: Cardiovasc Res. 2006 Sep 1;71(4):794-802
references: 16822492
references: J Hypertens. 2002 Jan;20(1):71-8
references: 11791028
references: J Hypertens Suppl. 2009 Aug;27(6):S27-31
references: 19633448
references: Nephrol Dial Transplant. 2003 Oct;18(10):1999-2004
references: 13679473
references: Gen Physiol Biophys. 2012 Sep;31(3):279-90
references: 23047941
references: J Cereb Blood Flow Metab. 2002 Oct;22(10):1239-47
references: 12368663