title: c-Src in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats.
abstract: Enhanced cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation in renovascular hypertension. The study was to determine whether c-Src in paraventricular nucleus (PVN) is involved in the enhanced CSAR and sympathetic activation in hypertensive rats induced by two-kidney one-clip (2K1C). At the end of the fourth week after 2K1C surgery, renal sympathetic nerve activity (RSNA) was recorded in anesthetized rats with baroreceptor denervation and vagotomy. The CSAR was evaluated by the RSNA response to epicardial application of capsaicin. In the PVN, c-Src activity was higher in 2K1C rats than sham-operated (Sham) rats while c-Src expression was not. Epicardial application of capsaicin or PVN microinjection of angiotensin II (Ang II) increased c-Src activity more in 2K1C than Sham rats. PVN microinjection of selective Src family kinase inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazol [3,4-D] pyrimidine (PP2) or 2,3-Dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1 H-indol-2-yl)methylene]-1 H-indole-5-sulfonamide (SU6656) abolished the CSAR and decreased RSNA more in 2K1C than Sham rats. The Ang II-induced RSNA and CSAR enhancement was abolished by PP2 or SU6656 pretreatment in 2K1C and Sham rats. NAD(P)H oxidase activity and superoxide anion level in PVN were higher in 2K1C rats, which was attenuated by PP2 but increased by epicardial application of capsaicin or PVN microinjection of Ang II. The effects of capsaicin or Ang II were abolished by PP2. These results indicate that c-Src in the PVN is involved in the enhanced CSAR and sympathetic activation in renovascular hypertension, and mediates the excitatory effects of Ang II in the PVN on the CSAR and sympathetic activity via NAD(P)H oxidase-derived generation of superoxide anions.
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.forename: Ning
authors.initials: N
authors.lastname: Yuan
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Gao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shi
authors.forename: Ye-Bo
authors.initials: YB
authors.lastname: Zhou
authors.forename: Xing-Ya
authors.initials: XY
authors.lastname: Gao
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Zhu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D006978:Hypertension, Renovascular / Q000378:metabolism / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012018:Reflex / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D019061:src-Family Kinases
chemical_list: C412373:AG 1879; D007211:Indoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C416927:SU 6656; D013449:Sulfonamides; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D002211:Capsaicin