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.

Association between duration of oral contraceptive use and risk of hypertension: A meta‐analysis

“…However, the detailed biological mechanisms underlying the association between oral contraceptive use and hypertension are still poorly understood. First, oral contraceptives can activate the renin‐angiotensin system by upregulation of intrarenal angiotensin‐converting enzyme 1 and angiotensin II type 1 receptor . Second, oral contraceptive use causes endothelial dysfunction by increasing circulating uric acid, impairing the endothelium‐dependent nitric oxide pathway and elevating proinflammatory biomarkers such as plasminogen activator inhibitor‐1 and C‐reactive protein .…”

Controlling resistant hypertension

“…Oral contraceptives cause hypertension; there may be several mechanisms. In a rat model combined hormonal therapy induced endothelial dysfunction and upregulation of the ACE-1 gene and angiotensin receptor gene 13 ; however, combined hormonal therapy in postmenopausal women raises the level of aldosterone and lowers the level of plasma renin. 14 …”

Experimental models for vascular endothelial dysfunction

“…A study stated that the ethinyl estradiol-treated experimental model reverses the relaxation to acetylcholine. The risk of hypertension in ethinyl estradiol-treated rats is accompanied by endothelial degradations and elevated levels of proinflammatory factors and RAAS (Olatunji et al, 2016). The administration of ethinyl estradiol is also considered as a factor for premature atherosclerosis, thrombogenesis and causes change in the endothelial structure and its function.…”