Mineralocorticoid receptor blocker usage among sleep apnea subjects with resistant hypertension

Background: African-Americans have the highest prevalence of elevated blood pressure (BP) and poorer BP control than other racial/ethnic groups in the US. Untreated sleep apnea, common among minority populations, may explain the high prevalence of uncontrolled BP. We studied the association of objective measurements of sleep apnea severity with resistant hypertension and uncontrolled BP among African-Americans in the Jackson Heart Study (JHS) Sleep Ancillary study. Methods: Between 2012 and 2016, JHS participants (N=913) underwent an in-home sleep apnea study (measuring nasal pressure, abdominal and thoracic inductance plethysmography, oximetry, position, ECG); resting blood pressure; anthropometry; and completed questionnaires. Sleep apnea was defined as an apnea-hypopnea index > 15 and nocturnal hypoxemia was quantified as % sleep time <90% oxyhemoglobin saturation (%Sat<90%). Elevated BP was defined as systolic BP ≥ 140 mmHg or diastolic BP > 90mmHg. Controlled BP was defined as systolic BP <140mmHg or diastolic BP <90mmHg. Uncontrolled BP was defined as having elevated BP with use of < 2 antihypertensive medications. Resistant hypertension was defined as having elevated BP while on 3-4 antihypertensive medications with one being a diuretic; or use of > 4 antihypertensive medications. The study sample was limited to individuals with prevalent hypertension (N=613). Multinomial models were fit to determine the association between sleep apnea severity and resistant hypertension or uncontrolled BP (vs. controlled BP) adjusted for age, sex, education, smoking status, obesity (body mass index>30) and diabetes. Results: The study sample had a mean age of 54.8 years, were predominately female (69.8%), obese (57.8%), and college educated (52.7%). Approximately 40.5% had sleep apnea, which was untreated in 95% of individuals. Among the sample, 25.4% had uncontrolled BP and 4.9% were classified as resistant hypertension. After adjustment for confounders, individuals with sleep apnea had a 2.6-fold higher odds of resistant hypertension (95% confidence interval: 1.1, 5.9). A standard deviation higher %Sat<90% was associated with a 41% higher odds (1.1, 1.8) of resistant hypertension after adjustment for covariates. Sleep apnea and %Sat<90% were not related to uncontrolled BP. Conclusion: Among our sample of African-Americans in the JHS, sleep apnea was related to resistant hypertension but not uncontrolled BP. The study identifies the high burden of untreated sleep apnea in African-Americans and its association with resistant hypertension, a significant risk factor for stroke and heart disease. Research is needed on the impact of treating sleep apnea as a strategy for decreasing resistant hypertension, and thus, narrowing cardiovascular health disparities.

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Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients With Resistant Hypertension and Sleep Apnea

Hypertension ◽

10.1161/hypertensionaha.111.173799 ◽

2011 ◽

Vol 58 (4) ◽

pp. 559-565 ◽

Cited By ~ 310

Author(s):

Adam Witkowski ◽

Aleksander Prejbisz ◽

Elżbieta Florczak ◽

Jacek Kądziela ◽

Paweł Śliwiński ◽

...

Keyword(s):

Blood Pressure ◽

Sleep Apnea ◽

Glycemic Control ◽

Resistant Hypertension ◽

Sympathetic Denervation ◽

Renal Sympathetic Denervation ◽

Renal Sympathetic

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Long-term Effect of CPAP Treatment on Cardiovascular Events in Patients With Resistant Hypertension and Sleep Apnea. Data From the HIPARCO-2 Study

Archivos de Bronconeumología ◽

10.1016/j.arbres.2019.12.006 ◽

2020 ◽

Author(s):

Cristina Navarro-Soriano ◽

Miguel-Angel Martínez-García ◽

Gerard Torres ◽

Ferrán Barbé ◽

Manuel Sánchez-de-la-Torre ◽

...

Keyword(s):

Sleep Apnea ◽

Resistant Hypertension ◽

Cardiovascular Events ◽

Term Effect ◽

Cpap Treatment ◽

Long Term Effect

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Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker

Hypertension Research ◽

10.1038/s41440-020-0495-0 ◽

2020 ◽

Vol 43 (11) ◽

pp. 1204-1213

Author(s):

Kiyoshi Arai ◽

Yuka Morikawa ◽

Naoko Ubukata ◽

Kotaro Sugimoto

Keyword(s):

Diabetic Nephropathy ◽

Blood Glucose ◽

Mineralocorticoid Receptor ◽

Antihypertensive Effect ◽

Urinary Albumin ◽

Receptor Blocker ◽

Angiotensin Ii Receptor Blocker ◽

Angiotensin Ii Receptor ◽

Ay Mice

AbstractEsaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin–angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (−1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

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Deficiency of T-type Ca2+ channels Cav3.1 and Cav3.2 has no effect on angiotensin II-induced hypertension but differential effect on plasma aldosterone in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00121.2018 ◽

2019 ◽

Vol 317 (2) ◽

pp. F254-F263

Author(s):

Anne D. Thuesen ◽

Stine H. Finsen ◽

Louise L. Rasmussen ◽

Ditte C. Andersen ◽

Boye L. Jensen ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Mineralocorticoid Receptor ◽

Plasma Aldosterone ◽

Receptor Blocker ◽

Ang Ii ◽

Induced Hypertension

T-type Ca2+ channel Cav3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Cav3.1, but not Cav3.2, protects mice against angiotensin II (ANG II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg−1·min−1, 7 days) in wild-type (WT), Cav3.1−/−, and Cav3.2−/− mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg−1·min−1) with and without the mineralocorticoid receptor blocker canrenoate. Cav3.1−/− and Cav3.2−/− mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Cav3.1 and Cav3.2−/− mice. ANG II increased significantly MAP in WT, Cav3.1−/−, and Cav3.2−/− mice with no differences between genotypes. Heart rate was significantly lower in Cav3.1−/− and Cav3.2−/− mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Cav3.1−/− compared with Cav3.2−/− mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Cav3.1−/− mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Cav3.1−/− mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Cav3.1and Cav3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Cav3.1, but not Cav3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.

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