Angiotensin II receptor antagonism: Losartan—sites and mechanisms of action

Triggle, David J.

doi:10.1016/0149-2918(95)80080-8

Cited by 17 publications

(10 citation statements)

References 89 publications

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“…sodium reabsorption; hypertension; sodium entry; ouabain ANGIOTENSIN II (ANG II) acting via the AT 1 receptor stimulates net sodium reabsorption in the proximal tubule of the kidney, which affects blood pressure, contributes to the development of hypertension (27,37,47), and is relevant to the treatment of heart failure (9). Sodium moves from the lumen of the tubule across a single layer of epithelial cells and into the peritubular capillaries via three major sodium transport mechanisms.…”

mentioning

confidence: 99%

Angiotensin II directly stimulates activity and alters the phosphorylation of Na-K-ATPase in rat proximal tubule with a rapid time course

Yingst¹,

Massey²,

Rossi³

et al. 2004

American Journal of Physiology-Renal Physiology

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We present evidence that Na-K-ATPase in the rat proximal tubule is directly activated by ANG II much faster than previously observed. Specifically, we show that a 2-min exposure to 0.1 and 1 nM ANG II slowed the rate of intracellular sodium accumulation in response to an increase in extracellular sodium added in the presence of gramicidin D. From these data, we show that ANG II directly stimulates Na-K-ATPase activity at rate-limiting concentrations of intracellular sodium. Under these same conditions, exposing proximal tubules to ANG II altered the amount of 32P incorporated into multiple phosphopeptides generated from a tryptic digest of the alpha-subunit of Na-K-ATPase. Na-K-ATPase was isolated from whole cell lysates by means of a ouabain-affinity column and then separated into its individual subunits by SDS-PAGE. Na-K-ATPase bound to the column in its E2 conformation and was eluted by altering its conformation to E1 using Na+ATP. Na-K-ATPase isolated from cells treated with ANG II eluted more easily from the ouabain-affinity column than Na-K-ATPase isolated from control cells, suggesting that ANG II decreased the affinity of Na-K-ATPase for ouabain. Thus ANG II rapidly stimulated the activity of Na-K-ATPase in 2 min or less by a mechanism that could involve changes in phosphorylation and conformation of Na-K-ATPase. We suggest that the physiological role for rapid direct activation of Na-K-ATPase is greater control of intracellular sodium during sodium reabsorption.

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mentioning

confidence: 99%

Angiotensin II directly stimulates activity and alters the phosphorylation of Na-K-ATPase in rat proximal tubule with a rapid time course

Yingst¹,

Massey²,

Rossi³

et al. 2004

American Journal of Physiology-Renal Physiology

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“…Angiotensin is a potent pressor agent in all mammals [4], whilst BK is an endotheliuln-dependent vasodilator [2,5]. Moreover, multiple pathobiological effects of kinins and AT II are well documented, indicating that appropriate antagonists could be effective in disease states that include cardiac hypertrophy, hypertension, arthritis, asthma and chronic pain [2,3,7,8]. Moreover, the biological actions of AT II and BK are intrinsically linked by the action of angiotensin converting enzyme (EC 3.415.1, ACE).…”

Section: Introductionmentioning

confidence: 99%

Biochemical pharmacology of total retro-inverso analogues of bradykinin and angiotensin II: Molecular recognition by G-protein-coupled receptors and angiotensin converting enzyme

Howl

Wheatley

1998

Lett Pept Sci

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Total retro-inverso (TRI) analogues of bradykinin (BK), the B2a-selective kinin antagonist D-Arg~ -Phe7,Leu8]BK, angiotensin II (AT II) and the AT II antagonist Saralasin ([Sarl,ValS,AlaS]AT II) were prepared by conventional solid-phase synthesis. Molecular recognition of TRI peptidomimetics by G-protein-coupled receptors was studied by competitive radioligand displacement experiments. TRI analogues of D-Arg~ -Phe7,Leu8]BK specifically bound to the kidriey medulla B2a bradykinin receptor with affinities (Ka) ranging from 64/zM to 4/zM. Conversely, TRI analogues of BK, AT II and Saralasin did not bind to either the B2a bradykinin receptor or the rat ATla AT II receptor, respectively. These studies indicate that the TRI strategy is more compatible with the synthesis of antagonists than 'agonists'. Three TRI peptidomimetics of D-Arg~ were weak inhibitors of angiotensin converting enzyme. All other TRI peptidomimetics had no effect upon ACE activity. These data endorse the utility of the TRI strategy for the synthesis of protease-resistant antagonists of peptide hormones and neuropeptides.

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“…In the same year, the combination of losartan and low-dose hydrochlorothiazide was approved by FDA, with advantage of better blood pressure-lowering effects for patients whose blood pressure can not be controlled by the monotherapy [2]. After two-one side t-test following ANOVA to C max , AUC 0-12 and AUC 0-inf , no significant difference was found among losartan, E3174 and hydrochlorothiazide for test and reference formulation of losartan 50 mg and 50 mg losartan/12.5 mg hydrochlorothiazide in 20 healthy volunteers.…”

Section: Bioequivalence Evaluatementioning

confidence: 99%

“…Losartan, 2-n-butyl-4-cholo-5-hydroxymethyl-1-[(2%-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl] imidazole ( Figure 1), an active and highly specific non-peptide angiotensin II receptor blocker, is applied for treating hypertension in clinic [1,2]. After oral administration, losartan undergoes substantial first-pass metabolism by CYP2C9, and then approximately 14% of it is converted to the pharmacologically active metabolite E3174 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Hydrochlorothiazide, Losartan and E3174 after Oral Doses of Losartan and Losartan/Hydrochlorothiazide in Healthy Chinese Male Volunteers

Li¹,

Bu²,

Wei³

et al. 2012

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Aims: A simple and highly sensitive LC-MS method was used to determine the concentrations of losartan, its major active metabolite E3174 and hydrochlorothiazide in human plasma and pharmacokinetic characteristics and metabolism phenotype observation after administration of losartan tablets and losartan/hydrochlorothiazide combination tablets.Methods: An open, randomized cross-over single-dose study was designed in forty healthy male volunteers, A single-dose of 50 mg losartan tablets or 50 mg losartan/12.5 mg hydrochlorothiazide combination tablets was orally given and blood samples were collected at scheduled time. A LC-MS method was established and evaluated for determining the plasma concentrations of losartan, E3174 and hydrochlorothiazide. The pharmacokinetic parameters and characteristic of metabolism phenotypes were calculated and compared via this test. Results: The elimination rate of E3174 (t 1/2 ) was significantly shorter (P < 0.05) and the AUC 0-t was lower (P < 0.05) for administration of combination tablets. The rest of pharmacokinetic parameters of losartan and E3174 have no significant differences. Among all subjects, three phenotypes were observed: the poor, the intermediate and the extensive metabolism. Conclusion: It is indicated that the test and reference tablets were bioequivalent, and that hydrochlorothiazide could significantly alter the t 1/2 , AUC 0-t and AUC 0-inf of E3174.

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Angiotensin II receptor antagonism: Losartan—sites and mechanisms of action

Cited by 17 publications

References 89 publications

Angiotensin II directly stimulates activity and alters the phosphorylation of Na-K-ATPase in rat proximal tubule with a rapid time course

Angiotensin II directly stimulates activity and alters the phosphorylation of Na-K-ATPase in rat proximal tubule with a rapid time course

Biochemical pharmacology of total retro-inverso analogues of bradykinin and angiotensin II: Molecular recognition by G-protein-coupled receptors and angiotensin converting enzyme

Pharmacokinetics of Hydrochlorothiazide, Losartan and E3174 after Oral Doses of Losartan and Losartan/Hydrochlorothiazide in Healthy Chinese Male Volunteers

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