Significance of the Vascular Concentration of Angiotensin II–Receptor Blockers on the Mechanism of Lowering Blood Pressure in Spontaneously Hypertensive Rats

Jin, Denan; Saito, Hiroshi; Takubo, Takayuki; Nakanishi, Toyofumi

doi:10.1254/jphs.13167fp

Cited by 10 publications

(3 citation statements)

References 21 publications

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“…Among the many angiotensin receptor blockers (ARBs), azilsartan has been reported to be lipophilic and have a high affinity for tissues (18). Therefore, we used it to block the cardiac tissue angiotensin II AT1 receptor in SHRs.…”

Section: Protocol 1 (Effect Of Azilsartan)mentioning

confidence: 99%

Azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in spontaneously hypertensive rats

et al. 2018

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We examined whether the stimulation of the angiotensin II AT1 receptor increases the expression of the cardiac (pro)renin receptor ((P)RR) and its downstream signals and whether the blockade of the angiotensin II AT1 receptor by azilsartan decreases the expression of the cardiac (P)RR and its signaling in spontaneously hypertensive rats (SHRs) with a high-salt intake. Rats received normal-salt (0.9%) chow, high-salt (8.9%) chow, normal-salt chow with 1 mg/day of azilsartan, and high-salt chow with 1 mg/day of azilsartan from 6 to 12 weeks of age. Rats with normal-salt chow were administered 100 ng/kg/min of angiotensin II by osmotic minipump from 6 to 12 weeks of age. A high-salt diet and angiotensin II significantly increased the systolic blood pressure; overexpressed cardiac (P)RR, phosphorylated (p)-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1; enhanced cardiac interstitial and perivascular fibrosis, cardiomyocyte size, interventricular septum (IVS) thickness, and left ventricular (LV) end-diastolic dimension; and decreased LV fractional shortening. Azilsartan decreased systolic blood pressure, cardiac expressions of (P)RR, p-ERK1/2, p-p38MAPK, p-HSP27, and TGF-ß1, cardiac interstitial and perivascular fibrosis, cardiomyocyte size, and LV diastolic dimension, and improved LV fractional shortening. In conclusion, azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in SHRs.

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Section: Protocol 1 (Effect Of Azilsartan)mentioning

confidence: 99%

Azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in spontaneously hypertensive rats

et al. 2018

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“…Azilsartan has a higher affinity for and slower dissociation from angiotensin II type 1 receptors than other ARBs 12 . Indeed, azilsartan exhibits 3.1 times higher affinity for arteries than candesartan even after a drug washout 13 . Our retrospective study showed that azilsartan improves LV diastolic dysfunction more than candesartan in patients with HF 14 , suggesting as well as inspiring us to prospectively evaluate azilsartan’s effects compared with candesartan on LV diastolic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of azilsartan on left ventricular diastolic dysfunction compared with candesartan: J-TASTE randomized controlled trial

Ito

Takahama

Asakura

et al. 2023

Sci Rep

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Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient’s conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e′) (E/e′). Adjusted least-squares mean (LSM) change in E/e′ was − 0.8 (95% confidence interval [CI] − 1.49 to − 0.04) in the azilsartan group and 0.2 (95% CI − 0.49 to 0.94) in the candesartan group, providing the LSM differences of − 1.0 (95% CI − 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was – 2.7 mL/m2 with azilsartan vs 1.4 mL/m2 with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required.

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“…Among ARBs, azilsartan has been reported to show higher affinity for the angiotensin II type 1 (AT1) receptor [ 4 ] and better tissue penetration [ 5 , 6 ] compared to current agents, being the first drug to demonstrate statistically significant superiority in head-to-head comparison with another ARB [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Improvement of Diurnal Blood Pressure Variation by Azilsartan

et al. 2018

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BackgroundAzilsartan is an angiotensin II receptor blocker with a potent antihypertensive effect.MethodsIn a multicenter, prospective, open-label study, 265 patients with poor blood pressure control despite treatment with other angiotensin II receptor blockers were switched to 20 mg/day of azilsartan (patients on standard dosages) or 40 mg/day of azilsartan (patients on high dosages).ResultsBlood pressure was 149/83 mm Hg before switching and was significantly reduced from 1 month after switching until final assessment (132/76 mm Hg, P < 0.001). The pulse rate was 72/min before switching and increased significantly from 3 months after switching until final assessment (74/min, P < 0.005). A significant decrease of home morning systolic and diastolic pressure was observed from 1 and 3 months, respectively. Home morning blood pressure was 143/82 mm Hg before switching and 130/76 mm Hg at final assessment (P < 0.01). The morning-evening difference of systolic blood pressure decreased from 14.6 to 6.6 mm Hg after switching (P = 0.09). The estimated glomerular filtration rate was significantly decreased at 3, 6, and 12 months after switching, and serum uric acid was significantly increased at 12 months. No serious adverse events occurred.ConclusionAzilsartan significantly reduced the blood pressure and decreased diurnal variation in patients responding poorly to other angiotensin II receptor blockers.

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Significance of the Vascular Concentration of Angiotensin II–Receptor Blockers on the Mechanism of Lowering Blood Pressure in Spontaneously Hypertensive Rats

Cited by 10 publications

References 21 publications

Azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in spontaneously hypertensive rats

Azilsartan attenuates cardiac damage caused by high salt intake through the downregulation of the cardiac (pro)renin receptor and its downstream signals in spontaneously hypertensive rats

Efficacy of azilsartan on left ventricular diastolic dysfunction compared with candesartan: J-TASTE randomized controlled trial

Improvement of Diurnal Blood Pressure Variation by Azilsartan

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