In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist

Koike, Hiroyuki; Sada, Toshio; Mizuno, Makoto

doi:10.1097/00004872-200106001-00002

Cited by 78 publications

(64 citation statements)

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“…19,20 Our findings support the idea that olmesartan acts within the brain directly or indirectly and reduces oxidative stress in a hypertensive model. Consistent with our findings, chronic administration of olmesartan attenuates the exaggerated pressor response to L-glutamate in the RVLM of SHR.…”

Section: Discussionsupporting

confidence: 83%

“…17,18 Olmesartan is a strong AT1-receptor blocker with a high degree of insurmountability. 19,20 We hypothesized that systemic administration of olmesartan reduces oxidative stress in the brain, as well as in the peripheral vasculature, 21 and that this antioxidant action may account for the absence of reflex-induced sympathoexcitation after treatment with olmesartan. To examine this, we applied the technique of in vivo electron spin resonance (ESR) spectroscopy, 22 because the ESR method is a powerful technique for evaluating oxidative stress noninvasively 22,23 and is useful for assessing drug effects when applied in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

et al. 2009

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We previously showed that oxidative stress in the brain is involved in the neural mechanisms of hypertension. Therefore, olmesartan, an angiotensin type 1 receptor blocker, might affect oxidative stress in the brains of stroke-prone spontaneously hypertensive rats (SHRSP). Here, we evaluated the effects of olmesartan treatment using an in vivo electron spin resonance (ESR)/spin probe technique. Two groups of SHRSP were treated with either olmesartan (10 mg kg À1 day À1 ) or hydralazine (Hyd, 20 mg kg À1 day À1 )/hydrochlorothiazide (HCT, 4.5 mg À1 kg day À1 ) for 30 days (n¼5 for each). Systolic blood pressure decreased similarly in both groups after treatment. Heart rate and urinary norepinephrine (NE) excretion increased in rats treated with Hyd/HCT, but not in those treated with olmesartan. The in vivo ESR signal decay rates of the blood-brain barrierpermeable spin probe methoxycarbonyl-PROXYL were significantly higher in SHRSP brains than in age-matched normotensive Wistar-Kyoto rat brains (Po0.01; n¼6 for each). Olmesartan attenuated the ESR signal decay rates in SHRSP brains, but Hyd/HCT did not. Intracerebroventricular infusion of active form of olmesartan, RNH-6270, reduced blood pressure and NE excretion, and the ESR signal decay rate was reduced in SHRSP brains. These findings indicate that olmesartan has anti-oxidative property in the brain without stimulating reflex-mediated sympathetic activity in SHRSP.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

et al. 2009

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“…The affinity of olmesartan for the AT 1 receptor is higher than that of, for example, losartan (IC 50 92 ± 5 nmol/l). 2 …”

Section: Introductionmentioning

confidence: 99%

The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview

Brunner

2002

J Hum Hypertens

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The new orally active angiotensin II (A II) type-1 receptor antagonist olmesartan medoxomil is a prodrug, which is rapidly converted in vivo to the active metabolite, olmesartan. The pharmacology, antihypertensive efficacy and safety of olmesartan medoxomil and/or the pharmacologically active metabolite, olmesartan, have been evaluated in both non-clinical and clinical models. Orally administered olmesartan medoxomil is rapidly absorbed from the gastrointestinal tract and converted during absorption to olmesartan, which is subsequently excreted without further metabolism. Peak plasma concentrations of olmesartan occur 1-3 h after administration, after which concentrations decrease with an elimination half-life of 10-15 h. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets is 28.6%. In a single-dose crossover study in 16 patients with mild-to-moderate hypertension receiving a sodium-restricted diet, statistically significant lowering

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“…15,[21][22][23] In addition, in human volunteers, administration of olmesartan medoxomil 10-40 mg/day blocked the hypertensive response to exogenously administered angiotensin I by greater than 75% for 24 h, compared to controls. 5 …”

Section: Pharmacodynamic Profilementioning

confidence: 92%

“…Olmesartan has 100 000 times greater affinity for the Ang II type 1 receptor AT1 compared to the AT2 receptor, to which it binds competitively and insurmountably. 15,16 In in vitro studies, the concentration of olmesartan medoxomil required to produce a 50% inhibition of Ang II binding to AT1 receptor (IC 50 ) was 8.070.8 nmol/l, whereas the amount of the drug needed to produce the same IC50 binding of Ang II to the AT2 receptor was greater than 100 000 nmol/l. After oral administration, olmesartan medoxomil given in single doses of 10-160 mg in healthy volunteers, reaches a maximal concentration (C max ) within a maximal time of 1.4-2.8 h. 17,18 Both the C max and the mean area under the plasma concentration curve (AUC) showed similar linear relationships to the doses given and they were not significantly affected after multiple dose administration.…”

Section: Pharmacokinetic and Pharmacodynamic Profilementioning

confidence: 99%

Treatment of hypertension with olmesartan medoxomil, alone and in combination with a diuretic: an update

2007

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Olmesartan medoxomil is an angiotensin II (Ang II) receptor blocker (ARB) that has been approved by the US Food and Drug Administration (FDA) for the treatment of hypertension. It is a prodrug that is hydrolysed in the gut into its active metabolite, olmesartan (RNH-6270). Olmesartan is highly selective for the Ang II type 1 receptor (AT1) to which it binds completely and insurmountably and has very little affinity for the other receptor subtypes AT2 and AT4. After oral administration, in animals and humans, it achieves a maximal blood drug concentration within a maximal time of approximately 2 h. It is then slowly eliminated in the urine and faeces. His half-life is approximately 13 h, which makes it suitable for once-daily administration. Olmesartan medoxomil given orally in single daily doses of 20-40 mg has demonstrated significant blood pressure (BP) lowering effects in hypertensive patients. A medline search for the preparation of this manuscript was conducted and revealed 128 references, from 2000 to 2007. Of these, only 16 well-designed prospective clinical trials were selected. The remaining were either animal studies, reviews or studies in progress. In well-designed clinical trials, olmesartan medoxomil has demonstrated similar antihypertensive actions to the other antihypertensive drugs, as well as other members of its class given the highest recommended doses. In addition, the BP lowering effect of olmesartan, like the other members of its class, is greatly enhanced in combination with a diuretic. Its safety profile is similar to the other ARBs and no different than placebo.

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In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist

Cited by 78 publications

References 0 publications

Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview

Treatment of hypertension with olmesartan medoxomil, alone and in combination with a diuretic: an update

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