Brain AT1 Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand

Karamyan, Vardan T.; Gadepalli, Rama S; Rimoldi, John M.; Speth, Robert C.

doi:10.1124/jpet.109.157461

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…In addition, there were no differences in Ang II, its aminopeptidase-resistant analogs, and Ang III initial peak pressor responses, findings that do not support a requisite formation of Ang III to elicit a response. It has also been established that 125 I-Ang II can bind to brain AT 1 receptors, an effect that does not require conversion to 125 I-Ang III [28]. …”

Section: Discussionmentioning

confidence: 99%

“…AMA was selected since it is an APA inhibitor that is used by many investigators to study Ang II metabolism [26]. GluP was selected since it has recently received much attention as a direct APA inhibitor with a better selectivity for APA [28]. This enzyme was selected as a target for inhibition since it is the major enzyme involved in Ang II conversion to Ang III [26, 29].…”

Section: Discussionmentioning

confidence: 99%

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Distinct Molecular Effects of Angiotensin II and Angiotensin III in Rat Astrocytes

Clark

Nguyen²,

Tran³

2013

International Journal of Hypertension

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It is postulated that central effects of angiotensin (Ang) II may be indirect due to rapid conversion to Ang III by aminopeptidase A (APA). Previously, we showed that Ang II and Ang III induced mitogen-activated protein (MAP) kinases ERK1/2 and stress-activated protein kinase/Jun-terminal kinases (SAPK/JNK) phosphorylation in cultured rat astrocytes. Most importantly, both peptides were equipotent in causing phosphorylation of these MAP kinases. In these studies, we used brainstem and cerebellum astrocytes to determine whether Ang II's phosphorylation of these MAP kinases is due to the conversion of the peptide to Ang III. We pretreated astrocytes with 10 μM amastatin A or 100 μM glutamate phosphonate, selective APA inhibitors, prior to stimulating with either Ang II or Ang III. Both peptides were equipotent in stimulating ERK1/2 and SAPK/JNK phosphorylation. The APA inhibitors failed to prevent Ang II- and Ang III-mediated phosphorylation of the MAP kinases. Further, pretreatment of astrocytes with the APA inhibitors did not affect Ang II- or Ang III-induced astrocyte growth. These findings suggest that both peptides directly induce phosphorylation of these MAP kinases as well as induce astrocyte growth. These studies establish both peptides as biologically active with similar intracellular and physiological effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct Molecular Effects of Angiotensin II and Angiotensin III in Rat Astrocytes

Clark

Nguyen²,

Tran³

2013

International Journal of Hypertension

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“…The same group indeed subsequently showed that Ang II is an agonist for the rat brain AT 1 receptor and does not require prior conversion to Ang III [138].…”

Section: Angiotensin III and Angiotensin Ivmentioning

confidence: 94%

Brain angiotensin peptides regulate sympathetic tone and blood pressure

Dupont

Brouwers

2010

Journal of Hypertension

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Brain angiotensin II (Ang II) induces tonic sympathoexcitatory effects through AT1 receptor stimulation of glutamatergic neurons and sympathoinhibitory effects via GABAergic neurons in the rostral ventrolateral medulla, the brainstem 'pressor area'. NADPH-derived superoxide production and reactive oxygen species signalling is critical in these actions, and AT2 receptors in the rostral ventrolateral medulla appear to mediate opposing effects on sympathetic outflow. In the hypothalamic paraventricular nucleus, Ang II has AT1 receptor-mediated sympathoexcitatory effects and enhances nitric oxide formation, which in turn inhibits the Ang II effects through a GABAergic mechanism. Ang II also decreases the tonic sympathoinhibitory effect of gamma amino butyric acid within the paraventricular nucleus. Angiotensin III and Angiotensin IV increase blood pressure via brain AT1 receptor stimulation. Angiotensin (1-7) influences cardiovascular function through a specific Mas-receptor. This review examines the evidence that brain angiotensin peptides, glutamate, gamma amino butyric acid and nitric oxide interact within the rostral ventrolateral medulla and paraventricular nucleus to control sympathetic tone and blood pressure.

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“…Five of the slides from each set were then incubated in AM5 buffer containing a concentration of 125 I-SI Ang II ranging from 80 pM to 1900 pM in the presence of 10 μM PD123319 (a selective non-peptide AT 2 receptor antagonist) for 120 minutes. Under these conditions, all specific 125 I-SI Ang II binding is at the AT 1 receptor (Karamyan et al, 2009). The sixth slide from each set was incubated with 1900 pM 125 I-SI Ang II in the presence of an AT 1 receptor saturating concentration (3 μM) of Ang II for 120 minutes to determine non-specific binding of 125 I-SI Ang II.…”

Section: Methodsmentioning

confidence: 99%

Anteroposterior distribution of AT1 angiotensin receptors in caudal brainstem cardiovascular regulatory centers of the rat

2010

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Angiotensin II acts on Ang II type 1 (AT 1 ) receptors in areas of the caudal brainstem involved in cardiovascular regulation. In particular, activation of AT 1 receptors in the rostral ventrolateral medulla (RVLM) has been suggested to contribute to hypertension. However, the characteristics of AT 1 receptors in the RVLM of rat, the species in which the most experimental work has been done, is not well documented. This study evaluated AT 1 receptor binding along a 2.7 mm length of rat medulla, which included the full extent of the RVLM and the caudal ventrolateral medulla (CVLM). Sections of medulla from female rats cut on a cryostat were incubated with five concentrations of 125 I-sarcosine 1 ,isoleucine 8 angiotensin II to assess the density (Bmax) and dissociation constant (K D ) of the receptors for the radioligand. The dorsomedial medulla (DMM) displayed a high density of AT 1 binding (1207±100 fmol/g), which peaked at 0.4 mm rostral to the calamus scriptorius (approximately 14 mm caudal to Bregma). The RVLM and CVLM displayed significantly lower (p < 0.01) densities of AT 1 binding, 278±38 and 379±64 fmol/g, respectively. However, the dissociation constants were significantly lower (i.e., higher affinity) in RVLM and CVLM (164±38 and 178±27 pM, respectively,) than in DMM (328±12 pM, p < 0.01 and p < 0.05 respectively). These results provide an anatomical and pharmacological framework for future studies on the role in cardiovascular regulation of AT 1 receptors in the caudal brainstem.

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Brain AT1 Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand

Cited by 17 publications

References 37 publications

Distinct Molecular Effects of Angiotensin II and Angiotensin III in Rat Astrocytes

Distinct Molecular Effects of Angiotensin II and Angiotensin III in Rat Astrocytes

Brain angiotensin peptides regulate sympathetic tone and blood pressure

Anteroposterior distribution of AT1 angiotensin receptors in caudal brainstem cardiovascular regulatory centers of the rat

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