Pivotal role of angiotensin II receptor subtype 1A in the development of two-kidney, one-clip hypertension: study in angiotensin II receptor subtype 1A knockout mice.
OBJECTIVE
The present study was performed to examine in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice: first, the relative contribution of angiotensin II receptor subtypes 1A (AT(1A)) and 1B (AT(1B)); second, the role of angiotensin II type 2 (AT(2)) receptors in the development of hypertension in wild-type (AT(1A)+/+) and AT(1A) receptor knockout (AT(1A)-/-) mice; and third, the role of increased nitric oxide synthase activity in counteracting the hypertensinogenic action of angiotensin II in this model.


METHODS
AT(1A)+/+ and AT(1A)-/- mice underwent clipping of one renal artery and were infused with either saline vehicle or selective AT(2) receptor agonist CGP-42112A (CGP). Blood pressure was monitored by radiotelemetry. Blood pressure responses to the nitric oxide synthase inhibitor nitro-L-arginine-methyl-ester were evaluated.


RESULTS
AT(1A)+/+ mice responded to clipping by a rise in blood pressure that was not modified by CGP infusion. Clip placement caused a slight increase in blood pressure in AT(1A)-/- mice that remained significantly lower than in AT(1A)+/+ mice. Acute nitric oxide synthase inhibition caused greater increase in blood pressure in 2K1C/AT(1A)+/+ than in AT(1A)+/+ mice.


CONCLUSIONS
The present data support the critical role of AT(1A) receptors in the development of 2K1C hypertension, whereas AT(1B) receptors play only a minor role in blood pressure regulation in this model of angiotensin II-dependent hypertension. Activation of AT(2) receptors does not play an antagonistic role in the AT(1) receptor-mediated hypertensinogenic actions of angiotensin II in this model. Finally, enhanced nitric oxide synthase activity plays a protective role by counteracting the vasoconstrictor influences of angiotensin II in 2K1C hypertensive mice.
Cervenka
Ludek
L
Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. luce@medicon.cz
Vanecková
Ivana
I
Husková
Zuzana
Z
Vanourková
Zdenka
Z
Erbanová
Michaela
M
Thumová
Monika
M
Skaroupková
Petra
P
Opocenský
Martin
M
Malý
Jan
J
Chábová
Vera Certíková
VC
Tesar
Vladimír
V
Bürgelová
Marcela
M
Viklický
Ondrej
O
Teplan
Vladimír
V
Zelízko
Michal
M
Kramer
Herbert J
HJ
Navar
L Gabriel
LG
D000818:Animals; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D008026:Ligation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000502:physiology*; D012077:Renal Artery; D012084:Renin-Angiotensin System / Q000502:physiology*
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D019001:Nitric Oxide Synthase