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Combined oral contraceptive-induced hypertension is accompanied by endothelial dysfunction and upregulated intrarenal angiotensin II type 1 receptor gene expression

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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.

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) (2013R1A1A2058145, and 2013K2A4A1044932), funded by the Ministry of Education, Science and Technology; the Korean Health Technology R&D Project; Ministry of Health and Welfare, Republic of Korea (HI13C1527); and Kyungpook National University Research Fund, 2014.

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    Authors and Affiliations

    1. Department of Physiology, University of Ilorin, Ilorin, Nigeria

      Lawrence A. Olatunji

    2. Cardiovascular Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea

      Lawrence A. Olatunji, Young-Mi Seok, Adedoyin Igunnu, Seol-Hee Kang & In-Kyeom Kim

    3. National Development Institute of Korean Medicine, Hwarang-ro 94(Gapje-dong), Gyeongsan, Gyeongbuk, 38540, Republic of Korea

      Young-Mi Seok

    4. Department of Pharmacology, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea

      Seol-Hee Kang & In-Kyeom Kim

    5. Cell and Matrix Research Institute, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea

      Seol-Hee Kang & In-Kyeom Kim

    6. BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, 680 GukchaeBosang Street, Daegu, 41944, Republic of Korea

      Seol-Hee Kang & In-Kyeom Kim

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    Correspondence to In-Kyeom Kim.

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    All procedures were conducted in accordance with the Guiding Principles in the Care and Use of Laboratory Animals and approved by the Institutional Review Board, Kyungpook National University School of Medicine (KNU 2012-116). Every effort was made to minimize both the number of animals used and their suffering.

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    Lawrence A. Olatunji and Young-Mi Seok contributed equally to this work.

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    Olatunji, L.A., Seok, YM., Igunnu, A. et al. Combined oral contraceptive-induced hypertension is accompanied by endothelial dysfunction and upregulated intrarenal angiotensin II type 1 receptor gene expression. Naunyn-Schmiedeberg's Arch Pharmacol 389, 1147–1157 (2016). https://doi.org/10.1007/s00210-016-1272-0

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