Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation

Tsutsumi, Yoshio; Matsubara, Hiroaki; Masaki, Hiroya; Kurihara, Hiroki; Murasawa, Satoshi; Takai, Shinji; Miyazaki, Mizuo; Nozawa, Yoshihisa; Ozono, Ryoji; Nakagawa, Keigo; Miwa, Takeshi; Kawada, Noritaka; Mori, Yoshihide; Shibasaki, Yasunobu; Tanaka, Yasuaki; Fujiyama, Soichiro; Koyama, Yohko; Fujiyama, Atsuko; Takahashi, Hakuo; Iwasaka, Toshiji

doi:10.1172/jci7886

Cited by 513 publications

(420 citation statements)

References 56 publications

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“…Second, because AT 2 effects can be blocked by the specific B 2 antagonist icatibant, other studies have suggested that there might be interactions between AT 2 and the BK/B 2 system. 41,42 Nevertheless, further experiments are needed to arrive at a final conclusion.…”

Section: Impact Ofmentioning

confidence: 99%

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

et al. 2012

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The renin-angiotensin system (RAS) has a vital role in regulating the cardiovascular system. The primary effector of the RAS is the octapeptide angiotensin (Ang) II, a potent regulator of blood pressure and water homeostasis. Ang II mediates its functions through the stimulation of two distinct receptors, AT 1 (two subtypes in rodents (AT 1a and AT 1b )) and AT 2 . It was shown that in addition to Ang II, shorter fragments of Ang are also biologically active. Ang-(1-7) came into focus because it opposes many of the detrimental effects of Ang II. However, it is still controversial whether Ang II receptors are involved in Ang-(1-7)-mediated signaling. To characterize the impacts of Ang II receptors on Ang-(1-7)-stimulated vascular relaxation, the effects of acute infusion of the three vasorelaxant compounds, that is, Ang-(1-7), bradykinin (BK) and acetylcholine (ACh), on heart rate (HR) and mean arterial pressure (MAP) were investigated in mice deficient for one, two or all three Ang II receptors. Ang-(1-7) and BK reduced MAP in wild-type, AT 1a /AT 1b -deficient and AT 2 -deficient mice. Although the change in absolute MAP values in the hypotensive triple knockouts (KO) could not be further reduced by both peptides, the percent change in MAP was comparable between the triple KO and wild-type mice. Both peptides did not alter the HR in all four genotypes. ACh significantly reduced absolute MAP values in all four genotypes with a similar percentage of reduction. In contrast to Ang-(1-7) and BK, ACh significantly reduced HR without genotypic differences. Our results generate proof that Ang-(1-7)-induced effects on MAP are mediated by a receptor that is independent of AT 1 and AT 2 .

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Section: Impact Ofmentioning

confidence: 99%

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

et al. 2012

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“…The contribution of such an indirect AT 2 receptor stimulation to the actions of AT 1 receptor antagonists has been demonstrated in experimental models of hypertension, myocardial infarction or heart failure (Gohlke et al 1998;Van Kats et al 2000;Varagic et al 2001). In addition, several studies have revealed a contribution of bradykinin to the AT 1 receptor antagonist actions and suggested that stimulation of the AT 2 receptor leads to a bradykinin-dependent release of NO and subsequent generation of cyclic GMP Carey 1996, 1997;Gohlke et al 1998;Tsutsumi et al 1999).…”

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confidence: 99%

Contribution of bradykinin and nitric oxide to AT₂ receptor‐mediated differentiation in PC12 W cells

Zhao

Biermann

Luther

et al. 2003

Journal of Neurochemistry

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We investigated the effect of angiotensin II on intracellular cyclic GMP content and neurite outgrowth as an indicator of cell differentiation in PC12 W cells. Neurite outgrowth was examined by phase-contrast microscopy. Outgrown neurites were classified as small, medium and large, and were expressed as neurites per 100 cells. Angiotensin II (10 )7 M) increased the outgrowth of medium and large neurites by mean ± SEM 20.2 ± 2.3 and 6.6 ± 1.4 compared with 1.66 ± 0.5 and 0.1 ± 0.06 neurites per 100 cells in control. Cellular cyclic GMP content increased by 50-250% with angiotensin II at concentrations of 10 )6 -10 )4 M. Both blockade of AT 2 receptors and of nitric oxide synthase markedly reduced angiotensin II-induced neurite outgrowth and cyclic GMP production. In contrast, B 2 receptor blockade had no effect or even increased these angiotensin II effects. Sodium nitroprusside and 8-bromo-cyclic GMP both mimicked the effects of angiotensin II on cell differentiation. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both angiotensin II and 8-bromo-cyclic GMP. Our results demonstrate that angiotensin II can stimulate cell differentiation in PC12 W cells by nitric oxide-related and cyclic GMP-dependent mechanisms. The effects of angiotensin II on cell differentiation and cyclic GMP production were mediated via the AT 2 receptor and further enhanced by bradykinin B 2 receptor blockade. Keywords: angiotensin II, AT 2 receptor, cell differentiation, bradykinin, cyclic GMP, nitric oxide. Two major angiotensin II (Ang II) receptor subtypes, AT 1 and AT 2 , have been identified using specific receptor antagonists such as losartan and PD 123319. Most of the established physiological actions of Ang II, such as regulation of blood pressure and electrolyte homoeostasis, as well as its growth promoting actions, are mediated by the AT 1 receptor. However, results of recent studies in various tissues and cell lines have highlighted a number of actions of Ang II that are mediated by activation of AT 2 receptors, including growth inhibition, differentiation, apoptosis and nerve regeneration (Nakajima et al. 1995;Stoll et al. 1995;Yamada et al. 1996;Lucius et al. 1998).Two major strategies have been developed to block the renin-angiotensin system, first, the blockade of angiotensinconverting enzyme (ACE) by the action of ACE inhibitors and, second, the selective blockade of the AT 1 receptor by AT 1 receptor antagonists. ACE inhibitors inhibit the generation of Ang II and block the effects of the peptide on both the AT 1 and the AT 2 receptor. In addition, ACE inhibition in part prevents the degradation of bradykinin, leading to a stimulation of bradykinin B 2 receptor-mediated release of paracrine mediators, such as nitric oxide (NO) and/or prostaglandins. Bradykinin-mediated actions appear to be of major importance for the organ protective effects of ACE inhibitors . On the other hand, AT 1 receptor antagonists selectively block the AT 1 receptor, leave the AT 2 receptor unopposed and do...

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“…La relation entre l'activation du récepteur AT2 et la production de BK a été confirmée chez la souris surexprimant le récepteur AT2. L'activation du récepteur AT2 entraîne une diminution du pH intracellulaire qui active la kallicréine, induisant ainsi une production accrue de bradykinine aboutissant à la stimulation du RB2 [8].…”

Section: Rôle De La Bradykinine Dans Le Mécanisme D'action Des Iecunclassified

Bradykinine et néphroprotection

et al. 2007

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Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation

Cited by 513 publications

References 56 publications

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Contribution of bradykinin and nitric oxide to AT₂ receptor‐mediated differentiation in PC12 W cells

Bradykinine et néphroprotection

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Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation

Cited by 513 publications

References 56 publications

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Contribution of bradykinin and nitric oxide to AT2 receptor‐mediated differentiation in PC12 W cells

Bradykinine et néphroprotection

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Contribution of bradykinin and nitric oxide to AT₂ receptor‐mediated differentiation in PC12 W cells