Central Angiotensin-II Increases Blood Pressure and Sympathetic Outflow via Rho Kinase Activation in Conscious Rabbits.
Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The importance of Rho kinase as a mediator of the effects of angiotensin-II (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for 2 weeks via osmotic minipump: AngII, Rho kinase inhibitor Fasudil, AngII plus Fasudil, or a vehicle control. AngII increased mean arterial pressure over the course of the infusion, and this effect was prevented by the coadministration of Fasudil. AngII increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; coadministration of Fasudil abolished both of these effects. AngII increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil coinfusion prevented these effects. Each of these end points showed a statistically significant interaction between AngII and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by AngII and decreased by Fasudil. Taken together, these data indicate that hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central AngII are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympathoexcitatory cardiovascular diseases.
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (P.R.P., A.M.S., I.H.Z.); U.S. Army Institute of Surgical Research, Fort Sam Houston, TX (A.M.S.); and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (K.K.V.H.).
Peter R
PR
Pellegrino
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (P.R.P., A.M.S., I.H.Z.); U.S. Army Institute of Surgical Research, Fort Sam Houston, TX (A.M.S.); and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (K.K.V.H.).
Alicia M
AM
Schiller
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (P.R.P., A.M.S., I.H.Z.); U.S. Army Institute of Surgical Research, Fort Sam Houston, TX (A.M.S.); and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (K.K.V.H.).
Karla K V
KK
Haack
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (P.R.P., A.M.S., I.H.Z.); U.S. Army Institute of Surgical Research, Fort Sam Houston, TX (A.M.S.); and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (K.K.V.H.). izucker@unmc.edu.
Irving H
IH
Zucker
D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D003243:Consciousness / Q000502:physiology; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D011817:Rabbits; D011897:Random Allocation; D012084:Renin-Angiotensin System / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism*
D000804:Angiotensin II; D054460:rho-Associated Kinases
Rho-associated kinases; RhoA GTP-binding protein; angiotensin II; baroreflex; cardiovascular diseases; hypertension; intraventricular infusions
Drug Discov Today. 2010 Aug;15(15-16):622-9
20601092
Hypertension. 2005 Aug;46(2):360-5
16051902
J Pharmacol Exp Ther. 2008 Jul;326(1):278-85
18441251
Am J Physiol Regul Integr Comp Physiol. 2016 Jan 15;310(2):R156-66
26538235
Hepatology. 2007 Jul;46(1):242-53
17596891
Hypertension. 1990 Mar;15(3):274-83
2303285
J Neurol Sci. 2005 Nov 15;238(1-2):31-9
16005902
Int J Cardiol. 2009 Jul 10;135(3):302-7
18582965
PLoS One. 2009 Nov 26;4(11):e8045
19956681
Am J Physiol. 1991 Oct;261(4 Pt 2):R802-10
1681746
Arterioscler Thromb Vasc Biol. 2011 Aug;31(8):1898-907
21597004
Hypertension. 2004 Feb;43(2):306-11
14707159
Science. 1991 Jun 28;252(5014):1813-6
2063193
Eur Heart J. 2001 Jul;22(13):1136-43
11428854
Circulation. 2004 Jan 6;109(1):120-4
14662714
Hypertension. 2007 Nov;50(5):904-10
17846349
Biochim Biophys Acta. 2010 Dec;1802(12):1276-84
20460153
Hypertens Res. 2010 Oct;33(10):1038-43
20668455
Am J Physiol Heart Circ Physiol. 2010 Aug;299(2):H402-9
20511410
Heart. 2013 Feb;99(4):240-6
23257173
Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4):R863-71
15563576
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2328-36
11709399
J Comp Neurol. 2004 Oct 4;478(1):72-87
15334650
Clin Auton Res. 2015 Apr;25(2):125-31
25739473
Brain Res Bull. 1995;37(2):131-7
7606488
Am J Physiol. 1990 Sep;259(3 Pt 2):F466-73
2396671
Circ Res. 1989 Jul;65(1):63-70
2736740
Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1495-500
15371261
Curr Hypertens Rep. 2011 Apr;13(2):122-8
21274755
Hypertension. 2006 Dec;48(6):1005-11
17015773
Am J Physiol Heart Circ Physiol. 2012 Aug 1;303(3):H377-85
22661508
Circulation. 2005 May 31;111(21):2741-7
15927989
Circulation. 2005 May 31;111(21):2837-49
15927992
Physiology (Bethesda). 2015 Mar;30(2):148-58
25729060
Am J Physiol Regul Integr Comp Physiol. 2012 Feb 15;302(4):R424-32
22160544
Hypertension. 2007 Feb;49(2):373-9
17159083
Circulation. 2005 Sep 20;112(12):1763-70
16157767
Circulation. 2007 Jul 3;116(1):85-97
17606856
J Anat. 2016 Jan;228(1):203-13
26510706
J Immunol. 2008 May 1;180(9):6010-7
18424721
Free Radic Biol Med. 2014 Aug;73:299-307
24924945
Nat Neurosci. 2012 Oct;15(10):1391-8
22941110
Hypertension. 2014 May;63(5):1041-9
24516105
Surg Neurol. 2007 Aug;68(2):126-31; discussion 131-2
17586012
J Hypertens Suppl. 2006 Mar;24(1):S51-6
16601574
Am J Physiol Regul Integr Comp Physiol. 2006 Apr;290(4):R1035-43
16322353
Circulation. 2003 May 20;107(19):2493-8
12695293
Hypertension. 2001 Dec 1;38(6):1307-10
11751708
Science. 1998 Jan 23;279(5350):509-14
9438836
Drugs. 2014 Dec;74(18):2211-5
25414122
Am J Physiol Regul Integr Comp Physiol. 2002 Apr;282(4):R1044-53
11893608
Pharmacol Rev. 2015 Oct;67(4):1074-95
26419448
Circ Res. 2004 Jul 23;95(2):210-6
15192025
Nat Med. 2010 Feb;16(2):183-90
20098430
Am J Physiol Cell Physiol. 2009 Nov;297(5):C1062-70
19692654
Hypertension. 2005 Apr;45(4):717-23
15699459
Circ Res. 2003 Jun 27;92(12):1337-43
12791705
J Hypertens. 2011 Feb;29(2):373-9
21063203
Clin Exp Pharmacol Physiol Suppl. 1989;15:31-43
2680188
J Hypertens. 2014 Feb;32(2):331-8
24356540
J Hypertens. 2007 Feb;25(2):399-406
17211247
Am J Physiol Heart Circ Physiol. 2014 Jul 1;307(1):H97-109
24791786
N Engl J Med. 1992 Dec 31;327(27):1912-8
1454086
Am J Physiol Heart Circ Physiol. 2013 Sep 15;305(6):H843-55
23832698
Hypertension. 2010 Feb;55(2):228-30
20008674
J Cardiovasc Pharmacol. 2007 Jul;50(1):17-24
17666911
Am J Physiol. 1998 Nov;275(5 Pt 2):R1611-9
9791081
J Neurochem. 2014 Jun;129(5):816-26
24528233
Circ Res. 2005 Dec 9;97(12):1232-5
16339495
Hypertension. 1999 Oct;34(4 Pt 2):724-8
10523349
Atherosclerosis. 2009 Aug;205(2):517-21
19167712
N Engl J Med. 1984 Sep 27;311(13):819-23
6382011
Auton Neurosci. 2008 Nov 3;142(1-2):77-81
18762460
Hypertension. 2004 Feb;43(2):156-62
14732730
J Am Coll Cardiol. 2011 Aug 9;58(7):765-73
21816315
Hypertension. 2013 Mar;61(3):723-9
23283363
Circ Res. 2003 Oct 17;93(8):767-75
14500337