Published Online
on April 18, 2005

A more recent version of this article appeared on May 1, 2005

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Submitted on January 23, 2005
Revised on February 18, 2005

Angiotensin Type 2 Receptor-Mediated Phosphorylation of eNOS in the Aortas of Mice With 2-Kidney, 1-Clip Hypertension

Hiromi Hiyoshi; Katsutoshi Yayama^*; Masaoki Takano; and Hiroshi Okamoto

From the Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Ikawadani-cho, Nishi-ku, Kobe, Japan.

^* To whom correspondence should be addressed. E-mail: yayama{at}pharm.kobegakuin.ac.jp.

Abstract--To evaluate the role of vascular angiotensin II (Ang II) type 2 (AT₂) receptor in renovascular hypertension, we investigated expressions of AT₂ receptor and endothelial nitric oxide synthase (eNOS) in thoracic aortas of mice with 2-kidney, 1-clip (2K1C) hypertension. The mRNA levels of AT₂ receptor in aortas, but not those of AT₁ and bradykinin B₂ receptors, increased 14 days but not 42 days after clipping. The contractile response to Ang II (>0.1 µmol/L) was attenuated in aortic rings excised 14 days after clipping and was restored to that of rings from sham mice by antagonists of AT₂ receptor (PD123319) and B₂ receptor (icatibant). The aortic levels of total eNOS, phosphorylated eNOS at Ser¹¹⁷⁷ (p-eNOS), total Akt, and phosphorylated Akt at Ser⁴⁷³ (p-Akt) were increased in 2K1C mice on day 14, whereas only eNOS levels were increased on day 42. The aortic cGMP levels were 20-fold greater in 2K1C mice on day 14 compared with sham mice. Administration of nicardipine for 4 days before the excision of aortas 14 days after clipping not only reduced blood pressure but also decreased the aortic levels of eNOS, p-eNOS, Akt, p-Akt, and cGMP to sham levels, whereas the administration of PD123319 or icatibant to 2K1C mice decreased p-eNOS and cGMP to sham levels without affecting blood pressure and the levels of eNOS, Akt and p-Akt. These results suggest that vascular NO production is enhanced by increased eNOS phosphorylation via the activation of AT₂ receptors in the course of 2K1C hypertension.

Key words: angiotensin II • bradykinin • cyclic GMP • nitric oxide synthase • hypertension, renovascular

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