Bell–shaped concentration–response curve for myocardial stimulation by glucocorticoids

Sellevold, Olav F Münter; Jynge, Per

doi:10.1111/j.1399-6576.1989.tb02861.x

Cited by 5 publications

(1 citation statement)

References 27 publications

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“…The slight changes in stroke volume, ϮdP/dt, and CVR observed on perfusion with 11-deoxycortisol may be due to local myocardial conversion of 11-deoxycortisol into cortisol, a compound previously shown to have mild hemodynamic effects. 16, 45 Silvestre and colleagues 46 have demonstrated myocardial corticosterone synthesis. Therefore, it is possible that 11-deoxycortisol is being converted into cortisol within the heart by hydroxylation of its 11-␤ position and thus able to elicit its mild hemodynamic effects.…”

Section: Discussionmentioning

confidence: 99%

Rapid Effects of Aldosterone and Spironolactone in the Isolated Working Rat Heart

et al. 2002

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Abstract-Chronic administration of aldosterone promotes myocardial fibrosis in rats. The Randomized Aldactone Evaluation Study reported that the aldosterone antagonist spironolactone improved outcome in patients with congestive heart failure, suggesting a deleterious effect of aldosterone in the heart. Aldosterone has been shown to have rapid nongenomic effects in different tissues including the heart. However, the hemodynamic actions of aldosterone and spironolactone are not well characterized. In this study, we examined the hemodynamic effects of aldosterone and its receptor antagonist, spironolactone, in the isolated rat heart by use of the Langendorff-Neely technique. Perfusion with 10 nmol/L aldosterone increased contractility by 45% within 2 to 4 minutes (PϽ0.01). Similar to the aldosterone effect, 10 nmol/L spironolactone increased contractility by 41% (PϽ0.01). Furthermore, 100-fold molar excess of spironolactone did not block the aldosterone effect. Perfusion of aldosterone plus spironolactone resulted in the highest increase in contractility 106% (PϽ0.01). The threshold response for aldosterone occurred within physiological concentrations (0.5 to 1 nmol/L), and maximal contractility was achieved with 10 nmol/L aldosterone. For spironolactone, the threshold and maximal contractile responses occurred at concentrations readily achieved with clinical dosing, 0.1 to 0.5 nmol/L and 1.0 nmol/L, respectively. These data demonstrate that aldosterone and spironolactone have rapid, positive inotropic actions on the myocardium. Moreover, addition of spironolactone to aldosterone increased contractility beyond the maximal responses elicited by each agent when perfused alone, thus suggesting different pathways of action. Furthermore, the intrinsic inotropic effects of spironolactone might be relevant to the apparent beneficial effect this compound has in patients with congestive heart failure. Key Words: congestive heart failure Ⅲ renin-angiotensin system Ⅲ mineralocorticoids Ⅲ aldosterone Ⅲ fibrosis Ⅲ cardiac function T he renin-angiotensin-aldosterone system represents a compensatory mechanism functioning to improve cardiac output during heart failure. 1 Although initially beneficial, prolonged activation of the renin-angiotensin-aldosterone system may be detrimental. The elevated pressure and increased extracellular fluid volume increases the hemodynamic load on the heart, leading to compensatory cardiac remodeling. 2 Also, aldosterone acting alone or with other humoral factors can increase fibrosis in the heart independent of pressure. [2][3][4][5][6] The Randomized Aldactone Evaluation Study (RALES) demonstrated significant reductions in morbidity and mortality rates when spironolactone, the aldosterone mineralocorticoid receptor antagonist, was included in the treatment of heart failure. 7,8 The rationale for this therapy was based on reports of the ability of aldosterone to activate cardiac fibroblasts and initiate cardiac fibrosis. 2-6,9 -14 Because of the success of spironolactone in RALES, this agent is c...

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Section: Discussionmentioning

confidence: 99%

Rapid Effects of Aldosterone and Spironolactone in the Isolated Working Rat Heart

et al. 2002

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Non-genomic effect of glucocorticoids on cardiovascular system

Lee

Kim

Youm

et al. 2012

Pflugers Arch - Eur J Physiol

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Glucocorticoids (GCs) are essential steroid hormones for homeostasis, development, metabolism, and cognition and possess anti-inflammatory and immunosuppressive actions. Since glucocorticoid receptor II (GR) is nearly ubiquitous, chronic activation or depletion of GCs leads to dysfunction of diverse organs, including the heart and blood vessels, resulting predominantly from changes in gene expression. Most studies, therefore, have focused on the genomic effects of GC to understand its related pathophysiological manifestations. The nongenomic effects of GCs clearly differ from well-known genomic effects, with the former responding within several minutes without the need for protein synthesis. There is increasing evidence that the nongenomic actions of GCs influence various physiological functions. To develop a GC-mediated therapeutic target for the treatment of cardiovascular disease, understanding the genomic and nongenomic effects of GC on the cardiovascular system is needed. This article reviews our current understanding of the underlying mechanisms of GCs on cardiovascular diseases and stress, as well as how nongenomic GC signaling contributes to these conditions. We suggest that manipulation of GC action based on both GC and GR metabolism, mitochondrial impact, and the action of serum- and glucocorticoid-dependent kinase 1 may provide new information with which to treat cardiovascular diseases.

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Methylprednisolone attenuates inflammation, increase of brain water content and intracranial pressure, but does not influence cerebral blood flow changes in experimental pneumococcal meningitis

1994

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Bell–shaped concentration–response curve for myocardial stimulation by glucocorticoids

Cited by 5 publications

References 27 publications

Rapid Effects of Aldosterone and Spironolactone in the Isolated Working Rat Heart

Rapid Effects of Aldosterone and Spironolactone in the Isolated Working Rat Heart

Non-genomic effect of glucocorticoids on cardiovascular system

Methylprednisolone attenuates inflammation, increase of brain water content and intracranial pressure, but does not influence cerebral blood flow changes in experimental pneumococcal meningitis

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