title: Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide.
abstract: The present study tested the hypotheses that 1) nitric oxide (NO) is involved in attenuated responses to ANG II in female mice, and 2) there is differential expression of neuronal NO synthase (nNOS) in the subfornical organ (SFO) and paraventricular nucleus (PVN) in response to systemic infusions of ANG II in males vs. females. Aortic blood pressure (BP) was measured in conscious mice with telemetry implants. N(G)-nitro-l-arginine methyl ester (l-NAME; 100 microg x kg(.-1)day(-1)), an inhibitor of NOS, was administrated into the lateral cerebral ventricle for 14 days before and during ANG II pump implantation. Central infusion of l-NAME augmented the pressor effects of systemic ANG II in females (Delta21.5 + or - 2.2 vs. Delta9.2 + or - 1.5 mmHg) but not in males (Delta29.4 + or - 2.5 vs. Delta30.1 + or - 2.5 mmHg). Central administration of N(5)-(1-imino-3-butenyl)-l-ornithine (l-VNIO), a selective nNOS inhibitor, also significantly potentiated the increase in BP induced by ANG II in females (Delta17.5 + or - 3.2 vs. Delta9.2 + or - 1.5 mmHg). In gonadectomized mice, central l-NAME infusion did not affect the pressor response to ANG II in either males or females. Ganglionic blockade after ANG II infusion resulted in a greater reduction in BP in central l-NAME- or l-VNIO-treated females compared with control females. Western blot analysis of nNOS protein expression indicated that levels were approximately 12-fold higher in both the SFO and PVN of intact females compared with those in intact males. Seven days of ANG II treatment resulted in a further increase in nNOS protein expression only in intact females (PVN, to approximately 51-fold). Immunohistochemical studies revealed colocalization of nNOS and estrogen receptors in the SFO and PVN. These results suggest that NO attenuates the increase in BP induced by ANG II through reduced sympathetic outflow in females and that increased nNOS protein expression associated with the presence of female sex hormones plays a protective role against ANG II-induced hypertension in female mice.
authors.affiliation: Department of Psychology, University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA. baojian-xue@uiowa.edu
authors.forename: Baojian
authors.initials: B
authors.lastname: Xue
authors.forename: Minati
authors.initials: M
authors.lastname: Singh
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.forename: Meredith
authors.initials: M
authors.lastname: Hay
authors.forename: Alan Kim
authors.initials: AK
authors.lastname: Johnson
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005730:Ganglionic Blockers / Q000008:administration & dosage; D018738:Hexamethonium / Q000008:administration & dosage; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009919:Orchiectomy; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives; D010052:Ovariectomy; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000201:enzymology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D012737:Sex Factors; D013356:Subfornical Organ / Q000187:drug effects / Q000201:enzymology*; D013564:Sympathetic Nervous System / Q000503:physiopathology; D013686:Telemetry; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; D005730:Ganglionic Blockers; C111862:N(5)-(1-imino-3-butenyl)ornithine; D011960:Receptors, Estrogen; D000804:Angiotensin II; D009569:Nitric Oxide; D018738:Hexamethonium; D009952:Ornithine; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D019331:NG-Nitroarginine Methyl Ester