title: Inhibition of neuregulin-1/ErbB signaling in the rostral ventrolateral medulla leads to hypertension through reduced nitric oxide synthesis.
abstract: BACKGROUND
  We recently reported that activation of neuregulin-1 (NRG-1)/ErbB signaling in the rostral ventrolateral medulla (RVLM) of the brainstem elicits sympathoinhibition and depressor effects, and ErbB2-type ErbB receptors are involved in the neurogenic mechanisms of hypertension. Nitric oxide (NO) in the RVLM also elicits sympathoinhibition and depressor effects. NRG-1 enhances NO synthase (NOS) expression in several tissues. Here, we tested the hypothesis that ErbB2 inhibition in the RVLM contributes to increasing blood pressure via modulating the effects of NOS.
  
  
  METHODS
  We measured the effects of chronic intracisternal infusion of an ErbB2 antagonist and local ErbB2 inhibition in the RVLM using RNA interference (ErbB2 siRNA) on blood pressure (BP), heart rate (HR), norepinephrine excretion (uNE), and NOS expression in the RVLM. The central effects of the ErbB2 antagonist or NRG-1β were investigated with or without chronic and acute prior administration of a NOS inhibitor.
  
  
  RESULTS
  Intracisternal infusion of the ErbB2 antagonist and ErbB2 siRNA increased BP, HR, and uNE; and reduced neuronal and endothelial NOS expression in the RVLM. Further, prior systemic administration of a NOS inhibitor abolished the pressor response to intracisternal infusion of an ErbB2 antagonist in awake rats. Prior injection of a NOS inhibitor or γ-aminobutyric acid-A receptor antagonist into the RVLM attenuated the depressor response to NRG-1 in anesthetized rats.
  
  
  CONCLUSIONS
  These findings indicate that inhibition of ErbB2 expression in the RVLM leads to hypertension, at least in part, by reducing NO synthesis and inhibiting γ-aminobutyric acid activity. NRG-1/ErbB signaling in the RVLM might exist upstream of NO synthesis.
authors: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors: Ryuichi
authors: R
authors: Matsukawa
authors: Yoshitaka
authors: Y
authors: Hirooka
authors: Koji
authors: K
authors: Ito
authors: Kenji
authors: K
authors: Sunagawa
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D009638:Norepinephrine / Q000652:urine; D051381:Rats; D011921:Rats, Inbred WKY; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D020890:Neuregulin-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009638:Norepinephrine; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C098214:tyrphostin AG825; C483804:Erbb2 protein, rat