Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons

Amit Modgil, Qi Zhang, Ajeeth Pingili, Neha Singh, Fanrong Yao, Jingyan Ge, Lirong Guo, Chengluan Xuan, Stephen T. O'Rourke, Chengwen Sun

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Abstract

Several studies have focused on the beneficial effects of peripheral angiotensin-(1-7) [Ang- (1-7)] in the regulation of cardiovascular function, showing its counterregulatory effect against the actions of angiotensin II (ANG II). However, its actions in the central nervous system are not completely understood. In the present study, we investigated the intracellular mechanisms underlying the action of ANG-(1-7) using the patchclamp technique in neurons cultured from the hypothalamus of neonatal spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Superfusion of neurons with ANG II (100 nM) significantly increased neuronal firing in both strains of rats, and this chronotropic effect of ANG II was significantly enhanced in prehypertensive SHR neurons compared with WKY rat neurons. The enhanced chronotropic effect of ANG II was attenuated by a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY 294002 (10 μM). Superfusion of neurons with ANG-(1-7) (100 nM) did not alter the neuronal firing rate in either SHR or WKY neurons; however, it significantly attenuated the chronotropic action of ANG II exclusively in prehypertensive SHR neurons. This counterregulatory effect of ANG-(1-7) on ANG II action in prehypertensive SHR neurons was attenuated by cotreatment with either A-779, a Mas receptor antagonist, or bisperoxovanadium, a phosphatase and tensin homologue deleted on chromosome ten (PTEN) inhibitor. In addition, incubation of WKY and prehypertensive SHR neurons with ANG-(1-7) significantly increased PTEN activity. The data demonstrate that ANG-(1-7) counterregulates the chronotropic action of ANG II via a PTEN-dependent signaling pathway in prehypertensive SHR neurons.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number5
DOIs
StatePublished - Mar 1 2012

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Inbred SHR Rats
Angiotensin II
Neurons
Inbred WKY Rats
7-Ala-angiotensin (1-7)
angiotensin I (1-7)
Phosphatidylinositol 3-Kinase
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphoric Monoester Hydrolases
Hypothalamus
Central Nervous System
Chromosomes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons. / Modgil, Amit; Zhang, Qi; Pingili, Ajeeth; Singh, Neha; Yao, Fanrong; Ge, Jingyan; Guo, Lirong; Xuan, Chengluan; O'Rourke, Stephen T.; Sun, Chengwen.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 5, 01.03.2012.

Research output: Contribution to journalArticle

Modgil, Amit ; Zhang, Qi ; Pingili, Ajeeth ; Singh, Neha ; Yao, Fanrong ; Ge, Jingyan ; Guo, Lirong ; Xuan, Chengluan ; O'Rourke, Stephen T. ; Sun, Chengwen. / Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons. In: American Journal of Physiology - Heart and Circulatory Physiology. 2012 ; Vol. 302, No. 5.
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AU - Modgil, Amit

AU - Zhang, Qi

AU - Pingili, Ajeeth

AU - Singh, Neha

AU - Yao, Fanrong

AU - Ge, Jingyan

AU - Guo, Lirong

AU - Xuan, Chengluan

AU - O'Rourke, Stephen T.

AU - Sun, Chengwen

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AB - Several studies have focused on the beneficial effects of peripheral angiotensin-(1-7) [Ang- (1-7)] in the regulation of cardiovascular function, showing its counterregulatory effect against the actions of angiotensin II (ANG II). However, its actions in the central nervous system are not completely understood. In the present study, we investigated the intracellular mechanisms underlying the action of ANG-(1-7) using the patchclamp technique in neurons cultured from the hypothalamus of neonatal spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Superfusion of neurons with ANG II (100 nM) significantly increased neuronal firing in both strains of rats, and this chronotropic effect of ANG II was significantly enhanced in prehypertensive SHR neurons compared with WKY rat neurons. The enhanced chronotropic effect of ANG II was attenuated by a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY 294002 (10 μM). Superfusion of neurons with ANG-(1-7) (100 nM) did not alter the neuronal firing rate in either SHR or WKY neurons; however, it significantly attenuated the chronotropic action of ANG II exclusively in prehypertensive SHR neurons. This counterregulatory effect of ANG-(1-7) on ANG II action in prehypertensive SHR neurons was attenuated by cotreatment with either A-779, a Mas receptor antagonist, or bisperoxovanadium, a phosphatase and tensin homologue deleted on chromosome ten (PTEN) inhibitor. In addition, incubation of WKY and prehypertensive SHR neurons with ANG-(1-7) significantly increased PTEN activity. The data demonstrate that ANG-(1-7) counterregulates the chronotropic action of ANG II via a PTEN-dependent signaling pathway in prehypertensive SHR neurons.

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