Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2008-10, Vol.295 (4), p.R1149-R1157
• Main Authors: Wang, Gang, Milner, Teresa A, Speth, Robert C, Gore, Andrea C, Wu, Di, Iadecola, Costantino, Pierce, Joseph P
• Format: Article
• Language: English
• Subjects: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; ACE inhibitors; Age Factors; Angiotensin II - pharmacology; Angiotensin II - physiology; Animals; Calcium; Calcium Channels, L-Type - metabolism; Calcium Signaling - drug effects; Calcium Signaling - physiology; Estradiol - pharmacology; Female; Gender differences; Hypertension; Losartan - pharmacology; Male; Medulla Oblongata - drug effects; Medulla Oblongata - metabolism; Medulla Oblongata - physiology; NADPH Oxidases - metabolism; Neurohumoral Control of Cardiovascular Function; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Nifedipine - pharmacology; Ovariectomy; Oxygen; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Risk factors; Rodents; Sex Factors; Signal Transduction - physiology; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.90485.2008

1 Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York; 2 Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York; 3 Department of Pharmacology, University of Mississippi School of Pharmacy, University of Mississippi, University, Mississippi; and 4 Division of Pharmacology and Toxicology, University of Texas, Austin, Austin Texas Submitted 9 June 2008 ; accepted in final form 29 July 2008 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. C1 neurons; reactive oxygen species; NADPH oxidase; calcium channel; estrogen Address for reprint requests and other correspondence: J. P. Pierce and G. Wang, Division of Neurobiology, Weill Corn