Sex-specific Effects of Spironolactone on Blood Pressure in Gonadectomized Male and Female Wistar Rats

Michaelis, Marten; Hofmann, Peter; Götz, Franziska; Bartel, C.; Kienitz, Tina; Quinkler, Marcus

doi:10.1055/s-0031-1299774

Cited by 9 publications

(6 citation statements)

References 21 publications

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“…This is supported by the finding that the observed sufficient reduction in blood pressure levels and UAE/Ucrea ratio in the eplerenone group was only achieved due to a significantly higher number of other antihypertensive drugs. In addition, the MR antagonist spironolactone is also an androgen receptor antagonist and its effectiveness and superiority in blood pressure lowering might also be caused by the additional androgen receptor blockade (43,44).…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Fourkiotis

Vonend²,

Diederich³

et al. 2013

European Journal of Endocrinology

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Objective: Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce. Design and methods: This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; nZ86); spironolactone (nZ65); and eplerenone (nZ18)). Results: GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications. Conclusions: Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

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Section: Discussionmentioning

confidence: 99%

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Fourkiotis

Vonend²,

Diederich³

et al. 2013

European Journal of Endocrinology

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“…In animal models, the aldosterone antagonists reduced the infarct size in male, but not female mice and rats (Rigsby et al ., ; Frieler et al ., ). Additionally, spironolactone was shown to lower BP only in male rats on a high‐salt diet (Michaelis et al ., ), whereas eplerenone is more effective in reducing myocardial infarct‐induced cardiac remodelling in female rats, and also, at restoring altered gene expression (Kanashiro‐Takeuchi et al ., ).…”

Section: Pharmacodynamics and Pharmacogenomicsmentioning

confidence: 99%

Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

Franconi

Campesi

2014

British J Pharmacology

211

143

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Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns. LINKED ARTICLESThis article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-3 Abbreviations ACEI, inhibitor of angiotensin converting enzyme; ADE, adverse drug effect; ARB, antagonist of angiotensin receptor 1; CV, cardiovascular; CYP, cytochrome P450 enzymes; ET-1, endothelin-1; HMG-CoA, hydroxymethylglutaryl coenzyme A; OC, oral contraceptives; RAS, renin angiotensin system; SGD, sex-gender difference IntroductionOptimal pharmacological therapy depends on many factors. Some of these factors are biological (metabolism, genetic and epigenetic backgrounds, age and sex) (Becquemont et al., 2006), while others depend on the environment such as care provider-patient relationship. In view of the numerous biological (sex) and psychosocial-cultural (gender) differences, women and men can be considered as two different categories (Legato, 2009). However, sex-gender difference (SGD) only started to acquire the right relevance in the latter part of the last century, although Hippocrates, describing the symptoms of gout, had written 'A woman does not take the gout unless her menses has stopped ' (Enomoto and Endou, 2005), indicating a SGD in susceptibility rather than the development of a disease. The first pharmacological SGD was described in 1932 (Nicholas and Barron, 1932), when it was demonstrated that the hypnotic effect of hexobarbital lasted longer in female than in male rats. Later, it was shown that this difference is dependent on the metabolic process (Quinn et al., 1958). Nowadays, SGDs in pharmacokinetic parameters are well known and have been recently and extensively (Gandhi et al., 2004;Anderson, 2005;Franconi et al., 2007; 2011a,b;Soldin and Mattison, 2009). The SGDs in pharmacodynamics are not so well-known, but the...

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“…In rats, a very high salt diet (4 % NaCl) significantly increases systolic blood pressure in both males and females. This effect can be blocked in males, but not females, by the MR antagonist spironolactone independently of gonadal steroids [114]. Females may thus also have different sensitivity to aldosterone, although how responses in the adrenal medulla differ is unclear [115][116][117].…”

Section: The Mr Is a Key Determinant Of Cardiac Fibrosismentioning

confidence: 99%

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

et al. 2013

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MR (mineralocorticoid receptor) activation in the heart plays a central role in the development of cardiovascular disease, including heart failure. The MR is present in many cell types within the myocardium, including cardiomyocytes, macrophages and the coronary vasculature. The specific role of the MR in each of these cell types in the initiation and progression of cardiac pathophysiology is not fully understood. Cardiomyocyte MRs are increasingly recognized to play a role in regulating cardiac function, electrical conduction and fibrosis, through direct signal mediation and through paracrine MR-dependent activity. Although MR blockade in the heart is an attractive therapeutic option for the treatment of heart failure and other forms of heart disease, current antagonists are limited by side effects owing to MR inactivation in other tissues (including renal targets). This has led to increased efforts to develop therapeutics that are more selective for cardiac MRs and which may have reduced the occurrence of side effects in non-cardiac tissues. A major clinical consideration in the treatment of cardiovascular disease is of the differences between males and females in the incidence and outcomes of cardiac events. There is clinical evidence that female sensitivity to endogenous MRs is more pronounced, and experimentally that MR-targeted interventions may be more efficacious in females. Given that sex differences have been described in MR signalling in a range of experimental settings and that the MR and oestrogen receptor pathways share some common signalling intermediates, it is becoming increasingly apparent that the mechanisms of MRs need to be evaluated in a sex-selective manner. Further research targeted to identify sex differences in cardiomyocyte MR activation and signalling processes has the potential to provide the basis for the development of cardiac-specific MR therapies that may also be sex-specific.

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Sex-specific Effects of Spironolactone on Blood Pressure in Gonadectomized Male and Female Wistar Rats

Cited by 9 publications

References 21 publications

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

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