title: Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons.
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 patch-clamp 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.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Modgil
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ajeeth
authors.initials: A
authors.lastname: Pingili
authors.forename: Neha
authors.initials: N
authors.lastname: Singh
authors.forename: Fanrong
authors.initials: F
authors.lastname: Yao
authors.forename: Jingyan
authors.initials: J
authors.lastname: Ge
authors.forename: Lirong
authors.initials: L
authors.lastname: Guo
authors.forename: Chengluan
authors.initials: C
authors.lastname: Xuan
authors.forename: Stephen T
authors.initials: ST
authors.lastname: O'Rourke
authors.forename: Chengwen
authors.initials: C
authors.lastname: Sun
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology*; D000808:Angiotensinogen / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017968:Vanadium Compounds / Q000494:pharmacology
chemical_list: C092006:7-Ala-angiotensin (1-7); C534933:Agt protein, rat; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010446:Peptide Fragments; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D000808:Angiotensinogen; D000804:Angiotensin II; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000803:Angiotensin I; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; C118790:angiotensin I (1-7)