title: Combined oral contraceptive-induced hypertension is accompanied by endothelial dysfunction and upregulated intrarenal angiotensin II type 1 receptor gene expression.
abstract: Combined oral contraceptive (COC) use is associated with increased risk of developing hypertension. Activation of the intrarenal renin-angiotensin system (RAS) and endothelial dysfunction play an important role in the development of hypertension. We tested the hypothesis that COC causes hypertension that is associated with endothelial dysfunction and upregulation of intrarenal angiotensin-converting enzyme 1 (Ace1) and angiotensin II type 1 receptor (At1r). Female Sprague-Dawley rats aged 12 weeks received (p.o.) olive oil (control) and a combination of 0.1 μg ethinylestradiol and 1.0 μg norgestrel (low COC) or 1.0 μg ethinylestradiol and 10.0 μg norgestrel (high COC) daily for 6 weeks. Blood pressure was recorded by tail cuff plethysmography. Expression of genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. COC treatment led to increased blood pressure, circulating uric acid, C-reactive protein and plasminogen activator inhibitor-1, renal uric acid, and expression of renal Ace1 and At1r. COC treatment resulted in increased contractile responses to phenylephrine in endothelium-denuded aortic rings. Endothelium-dependent relaxation responses to acetylcholine, but not endothelium-independent relaxation responses to nitric oxide (NO) donation by sodium nitroprusside, were attenuated in COC-exposed rings. Impaired relaxation responses to acetylcholine were masked by the presence of NO synthase inhibitor (L-NAME) in the COC-exposed rings, whereas the responses to acetylcholine in the presence of selective cyclooxygenase-2 inhibitor (NS-398) were enhanced. These findings indicate that COC induces hypertension that is accompanied by endothelial dysfunction, upregulated intrarenal Ace1 and At1r expression, and elevated proinflammatory biomarkers.
authors.affiliation: Department of Physiology, University of Ilorin, Ilorin, Nigeria.|Cardiovascular Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Olatunji
authors.affiliation: Cardiovascular Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.|National Development Institute of Korean Medicine, Hwarang-ro 94(Gapje-dong), Gyeongsan, Gyeongbuk, 38540, Republic of Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Seok
authors.affiliation: Cardiovascular Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.
authors.forename: Adedoyin
authors.initials: A
authors.lastname: Igunnu
authors.affiliation: Cardiovascular Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.|Department of Pharmacology, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.|Cell and Matrix Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Cardiovascular Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea. inkim@knu.ac.kr.|Department of Pharmacology, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea. inkim@knu.ac.kr.|Cell and Matrix Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea. inkim@knu.ac.kr.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea. inkim@knu.ac.kr.
authors.forename: In-Kyeom
authors.initials: IK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003277:Contraceptives, Oral, Combined; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D011464:Epoprostenol / Q000378:metabolism; D019304:Ethinyl Estradiol-Norgestrel Combination; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014527:Uric Acid / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D003277:Contraceptives, Oral, Combined; D018836:Inflammation Mediators; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014527:Uric Acid; D009569:Nitric Oxide; D019304:Ethinyl Estradiol-Norgestrel Combination; D011464:Epoprostenol; D007703:Peptidyl-Dipeptidase A
keywords: Gene expression; Inflammation; Nitric oxide; Renal angiotensin receptor; Uric acid; Vascular endothelium