Effect of angiotensin II type 1 receptor blockade on cardiac remodeling in angiotensin II type 2 receptor null mice.
To clarify the possible involvement of uninhibited angiotensin II (Ang II) type 2 (AT(2)) receptor stimulation in the effects of an Ang II type 1 (AT(1)) receptor blocker, valsartan, we examined the cardiovascular remodeling induced by aortic banding with the use of wild-type (Agtr2+) and AT(2) receptor null (Agtr2-) mice. Aortic banding caused cardiac hypertrophy in Agtr2+ and Agtr2- mice to a similar degree 6 weeks after surgery, whereas coronary arterial thickening and perivascular fibrosis were more exaggerated in Agtr2- mice. The AT(2) receptor was observed predominantly in the coronary arteries and perivascular region of Agtr2+ mice. Valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, suppressed cardiac hypertrophy similarly in both strains. Valsartan inhibited coronary arterial thickening and perivascular fibrosis in both groups; however, the inhibitory effects of valsartan were significantly weaker in Agtr2- mice. The inhibitory effects of a nonselective Ang II receptor antagonist, [Sar(1),Ile(8)]-Ang II, on cardiac hypertrophy, coronary artery thickening, and perivascular fibrosis were not significantly different in Agtr2+ and Agtr2- mice. These results suggest that the improvement by valsartan of coronary arterial thickening and perivascular fibrosis after pressure overload is caused by uninhibited AT(2) receptor stimulation in addition to AT(1) receptor blockade.
Wu
Lan
L
Department of Medical Biochemistry Ehime University School of Medicine, Ehime, Japan.
Iwai
Masaru
M
Nakagami
Hironori
H
Chen
Rui
R
Suzuki
Jun
J
Akishita
Masahiro
M
de Gasparo
Marc
M
Horiuchi
Masatsugu
M
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine