title: Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla.
abstract: Sex differences may play a significant role in determining the risk of hypertension. Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are involved in the tonic regulation of arterial pressure and participate in the central mechanisms of hypertension. Angiotensin II (ANG II) acting on angiotensin type 1 (AT(1)) receptors in RVLM neurons is implicated in the development of hypertension by activating NADPH oxidase and producing reactive oxygen species (ROS). Therefore, we analyzed RVLM bulbospinal neurons to determine whether there are sex differences in: 1) immunolabeling for AT(1) receptors and the key NADPH oxidase subunit p47 using dual-label immunoelectron microscopy, and 2) the effects of ANG II on ROS production and Ca(2+) currents using, respectively, hydroethidine fluoromicrography and patch-clamping. In tyrosine hydroxylase-positive RVLM neurons, female rats displayed significantly more AT(1) receptor immunoreactivity and less p47 immunoreactivity than male rats (P < 0.05). Although ANG II (100 nM) induced comparable ROS production in dissociated RVLM bulbospinal neurons of female and male rats (P > 0.05), an effect mediated by AT(1) receptors and NADPH oxidase, it triggered significantly larger dihydropyridine-sensitive long-lasting (L-type) Ca(2+) currents in female RVLM neurons (P < 0.05). These observations suggest that an increase in AT(1) receptors in female RVLM neurons is counterbalanced by a reduction in p47 levels, such that ANG II-induced ROS production does not differ between females and males. Since the Ca(2+) current activator Bay K 8644 induced larger Ca(2+) currents in females than in male RVLM neurons, increased ANG II-induced L-type Ca(2+) currents in females may result from sex differences in calcium channel densities or dynamics.
authors.affiliation: Division of Neurobiology, Weill Cornell Medical College, 411 East 69th St., New York, NY 10021, USA. gaw2001@med.cornell.edu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Gore
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Pierce
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000367:Age Factors; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010052:Ovariectomy; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D004958:Estradiol; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014446:Tyrosine 3-Monooxygenase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D009543:Nifedipine; D019808:Losartan