Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.

Ja, Millar; Fraser, Robert; Mason, P A; Leckie, Brenda J.; Cumming, A. M. M.; Robertson, J. I. S.

doi:10.1111/j.1365-2125.1984.tb02478.x

Cited by 7 publications

(4 citation statements)

References 23 publications

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“…In the present study, mice displayed no detectable adverse reaction although treated with doses of ESO 2–5 times higher than the maximal safe dose used in human studies 44–46 . Also, amiloride can be used at very high levels in humans without toxicity 47,48 . Clinical data on EIPA are still missing.…”

Section: Discussionmentioning

confidence: 58%

“… 44 , 45 , 46 Also, amiloride can be used at very high levels in humans without toxicity. 47 , 48 Clinical data on EIPA are still missing. However, the tolerability of EIPA is high in mice, as confirmed by Maidorn et al that used high doses of the drug, 29 suggesting that the chemical modifications present in EIPA do not increase the risk of adverse effects and that its translation to a clinical use is possible.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

et al. 2021

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Triple negative breast cancers (TNBCs) are very aggressive and have a poor prognosis due to lack of efficacious therapies. The only effective treatment is chemotherapy that however is frequently hindered by the occurrence of drug resistance. We approached this problem in vitro and in vivo on a triple negative and a hormone sensitive breast cancer cell lines: 4T1 and TS/A. A main defense mechanism of tumors is the extrusion of intracellular protons derived from the metabolic shift to glycolysis, and necessary to maintain an intracellular pH compatible with life. The resulting acidic extracellular milieu bursts the malignant behavior of tumors and impairs chemotherapy. Therefore, we investigated the efficacy of combined therapies that associate cisplatin (Cis) with proton exchanger inhibitors, such as esomeprazole (ESO) and 5‐(N‐ethyl‐N‐isopropyl)amiloride (EIPA). Our results demonstrate that in the 4T1 triple negative model the combined therapy Cis plus EIPA is significantly more effective than the other treatments. Instead, in the TS/A tumor the best therapeutic result is obtained with ESO alone. Remarkably, in both 4T1 and TS/A tumors these treatments correlate with increase of CD8+ T lymphocytes and dendritic cells, and a dramatic reduction of M2 macrophages and other suppressor myeloid cells (MDSC) in the tumor infiltrates.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

et al. 2021

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“…Most drugs that affect blood pressure and/or the renal handling of electrolytes may in¯uence the concentrations of renin and aldosterone.For example, the potassiumsparing diuretics spironolactone and amiloride have been reported to increase both renin and aldosterone. 86 By contrast, propranolol has been shown to decrease plasma renin activity, 87 whereas the loop diuretic, frusemide, increases aldosterone and renin concentrations. 88 Although higher aldosterone concentrations have been reported in patients on ACE inhibitors, the majority of studies have shown raised renin activities and low aldosterone concentrations.…”

Section: Patient Preparation and Biological Variationmentioning

confidence: 99%

Renin-angiotensin-aldosterone axis

1993

Journal of Endocrinology

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Renin, an aspartyl protease, catalyses the initial and rate-limiting step of the renin-angiotensin cascade the cleavage of angiotensin I from angiotensinogen. Although the central role of renin in cardiovascular homeostasis was appreciated long before the cloning of its cDNA and gene, the application of molecular techniques over the last decade has led to several advances in our understanding of its structure and functions. Important insights have been gained regarding the substrate specificity of renin (which has facilitated the development of clinically useful renin inhibitors), the transcriptional and translational regulation of renin production, and the nature of prorenin. The renin locus has been implicated as one of the determinants of hypertension in rodent models of genetic hypertension. Finally, the abilty to directly detect renin gene expression has provided a crucial means of determining the existence of and investigating the regulation and functions of tissue renin-angiotensin systems. The talk will focus on these novel aspects of the biology of renin.S 24 Angiotensin I-converting enzyme: New questions from recent structure/function studies. P. Corvol INSERM U36 -Collège de France -3, rue d'Ulm -75005 PARIS -FRANCE The molecular cloning of the somatic and germinal forms of angiotensin Iconverting enzyme (ACE) and recent structure/function studies have radically modified our knowledge of the structure, biosynthesis and expression of ACE and raised new important questions. Three questions will be discussed:1) The somatic enzyme contains two domains (N and C domains) which are both catalytically active and able to bind ACE inhibitors. However, it is not yet known whether each active site displays a distinct substrate specificity, even though the and C domains have a different chloride concentration requirement for catalytic activity and the domain a preference for the cleavage between Trp3 and Ser4 of LH-RH.2) ACE is anchored via its C-terminus by an -helix and can be solubilized by a proteolytic cleavage. However, the cellular localization, the identification of this putative proteolytic enzyme and the exact site(s) of ACE cleavages are unknown.3) Serum ACE (SACE) levels are genetically determined. A polymorphism of the ACE gene (VD) accounts for 47 % of the total SACE variance. There is a strong association between ACE gene polymorphism and the levels of SACE. This I/D polymorphism has been recently shown to be an independent risk factor in myocardial infarction in an epidemiological study. It remains to identify the ACE gene variant responsible for the genetic variation of SACE and putatively for increased ACE gene expression in tissues of the DD patients.

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“…86 By contrast, propranolol has been shown to decrease plasma renin activity, 87 whereas the loop diuretic, frusemide, increases aldosterone and renin concentrations. 88 Although higher aldosterone concentrations have been reported in patients on ACE inhibitors, the majority of studies have shown raised renin activities and low aldosterone concentrations.…”

Section: Aldosterone and Renin Measurements 271mentioning

confidence: 99%