Direct angiotensin II type 2 receptor stimulation in Nω-nitro-L-arginine-methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodeling.
Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent cardiovascular risk factor. Although the angiotensin II type 1 receptor blockade belongs to major antihypertensive and cardioprotective therapies, less is known about the effects of long-term stimulation of the angiotensin II type 2 receptor. Previously, compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved the outcome of myocardial infarction in rats along with anti-inflammatory properties. We investigated whether compound 21 alone or in combination with angiotensin II type 1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic remodeling in N(ω)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Male adult Wistar rats (n=65) were randomly assigned to control, L-NAME, L-NAME+compound-21, L-NAME+olmesartan, and L-NAME+olmesartan+compound-21 groups and treated for 6 weeks. We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration. Olmesartan completely prevented hypertension, PWV and wall thickness increase, and the increase of aortic stiffness and partly prevented hydroxyproline accumulation. Compound 21 partly prevented all of these alterations, yet without concomitant prevention of blood pressure rise. Although the combination therapy with olmesartan and compound 21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan-alone-treated rats, only in the combination group was complete prevention of increased hydroxyproline deposition achieved, resulting in even more pronounced stiffness reduction. We conclude that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening and collagen accumulation without preventing hypertension in rats with inhibited NO synthase. These effects were additive to angiotensin II type 1 receptor blockade, yet without additional blood pressure-lowering effect, and they seem to be NO and blood pressure independent.
Center for Cardiovascular Research, Charité-University Medicine, Hessische Str 3-4, 10115 Berlin, Germany. ludo@lfuk.sk
Ludovit
L
Paulis
Sophie T R
ST
Becker
Kristin
K
Lucht
Katja
K
Schwengel
Svetlana
S
Slavic
Elena
E
Kaschina
Christa
C
Thöne-Reineke
Björn
B
Dahlöf
Johannes
J
Baulmann
Thomas
T
Unger
U Muscha
UM
Steckelings
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006909:Hydroxyproline / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000009:adverse effects*; D000068557:Olmesartan Medoxomil; D011673:Pulsatile Flow / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013777:Tetrazoles; D013876:Thiophenes; D000068557:Olmesartan Medoxomil; D003094:Collagen; D006909:Hydroxyproline; D019331:NG-Nitroarginine Methyl Ester