Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation.
Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na(+)/H(+) exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.
Tsutsumi
Y
Y
Department of Medicine II, Kansai Medical University, Moriguchi, Osaka 570, Japan.
Matsubara
H
H
Masaki
H
H
Kurihara
H
H
Murasawa
S
S
Takai
S
S
Miyazaki
M
M
Nozawa
Y
Y
Ozono
R
R
Nakagawa
K
K
Miwa
T
T
Kawada
N
N
Mori
Y
Y
Shibasaki
Y
Y
Tanaka
Y
Y
Fujiyama
S
S
Koyama
Y
Y
Fujiyama
A
A
Takahashi
H
H
Iwasaka
T
T
D000199:Actins / Q000235:genetics; D000584:Amiloride / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D065168:Bradykinin Receptor Antagonists; D002462:Cell Membrane / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007705:Kinins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017540:Tunica Media / Q000502:physiology*; D014661:Vasoconstriction; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000199:Actins; D065168:Bradykinin Receptor Antagonists; D007093:Imidazoles; D007705:Kinins; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D011993:Recombinant Fusion Proteins; D000804:Angiotensin II; C073402:PD 123319; D000584:Amiloride; C065679:icatibant; D006152:Cyclic GMP; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester