Effects of oral administration of furosemide and torsemide in healthy dogs

Hori, Yuichi; Takusagawa, Fumihiko; Ikadai, Hiromi; Uechi, Masami; Hoshi, Fumio; Higuchi, Seiichi

doi:10.2460/ajvr.68.10.1058

Cited by 44 publications

(61 citation statements)

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“…In human, torasemide has been reported to inhibit transcardiac extraction of aldosterone in patients with congestive heart failure [37], an effect which might be due to inhibition of local aldosterone synthesis, that has been reported to be increased in human heart failure [38]. In vivo however, in both human and dogs, torasemide, as other diuretics, increases plasma aldosterone levels to compensate sodium loss [39], [40], [41]. Therefore, if MR is not properly antagonized, torasemide administration would likely increase MR activation through the rise in plasma aldosterone levels rather than decrease MR-mediated pathways.…”

Section: Discussionmentioning

confidence: 99%

The Diuretic Torasemide Does Not Prevent Aldosterone-Mediated Mineralocorticoid Receptor Activation in Cardiomyocytes

et al. 2013

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Aldosterone binds to the mineralocorticoid receptor (MR) and exerts pleiotropic effects beyond enhancing renal sodium reabsorption. Excessive mineralocorticoid signaling is deleterious during the evolution of cardiac failure, as evidenced by the benefits provided by adding MR antagonists (MRA) to standard care in humans. In animal models of cardiovascular diseases, MRA reduce cardiac fibrosis. Interestingly diuretics such as torasemide also appear efficient to improve cardiovascular morbidity and mortality, through several mechanisms. Among them, it has been suggested that torasemide could block aldosterone binding to the MR. To evaluate whether torasemide acts as a MRA in cardiomyocytes, we compared its effects with a classic MRA such as spironolactone. We monitored ligand-induced nuclear translocation of MR-GFP and MR transactivation activity in the cardiac-like cell line H9C2 using a reporter gene assay and known endogenous aldosterone-regulated cardiac genes. Torasemide did not modify MR nuclear translocation. Aldosterone-induced MR transactivation activity was reduced by the MRA spironolactone, not by torasemide. Spironolactone blocked the induction by aldosterone of endogenous MR-responsive genes (Sgk-1, PAI-1, Orosomucoid-1, Rgs-2, Serpina-3, Tenascin-X), while torasemide was ineffective. These results show that torasemide is not an MR antagonist; its association with MRA in heart failure may however be beneficial, through actions on complementary pathways.

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Section: Discussionmentioning

confidence: 99%

The Diuretic Torasemide Does Not Prevent Aldosterone-Mediated Mineralocorticoid Receptor Activation in Cardiomyocytes

et al. 2013

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“…In contrast to furosemide, previous studies have revealed that long-acting loop diuretics have clinical efficacy; they cause less activation of the RAA system, reduce diuretic resistance, improve ventricular fibrosis and decrease the mortality rate in both humans and animal models [7,17,23,37]. Furosemide treatment for 14 days leads to diuretic resistance in dogs, but this does not occur with torasemide [17].…”

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confidence: 88%

“…Although furosemide is commonly used in clinical settings, its main complication is that patients with CHF develop resistance to loop diuretics due to a reduction in the glomerular filtration rate and an increase in sodium reabsorption at diuretic-insensitive sites in the nephron [6,10,11,28]. Additionally, furosemide activates the renin-angiotensinaldosterone (RAA) system and the sympathetic nervous system [14,16,32].In contrast to furosemide, previous studies have revealed that long-acting loop diuretics have clinical efficacy; they cause less activation of the RAA system, reduce diuretic resistance, improve ventricular fibrosis and decrease the mortality rate in both humans and animal models [7,17,23,37]. Furosemide treatment for 14 days leads to diuretic resistance in dogs, but this does not occur with torasemide [17].…”

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confidence: 92%

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Differences in the Duration of Diuretic Effects and Impact on the Renin-Angiotensin-Aldosterone System of Furosemide in Healthy Dogs

Hori

Ohshima

Kanai

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. Our aim was to investigate the differences in the duration of diuretic effects and impact on the renin-angiotensin-aldosterone (RAA) system of furosemide as a model of short-and long-acting loop diuretics. Anesthetized dogs (n=6) were randomized into placebo, intravenous bolus administration (IB) and chronic rate infusion (CRI) groups. This study was conducted with a crossover study. Furosemide (4 mg/kg) was diluted to 18 mL in sterile saline. Furosemide was infused at 0.5 mg/kg/hr for 8 hr in the CRI group or was injected at 0 and 4 hr (both 2 mg/kg) in the IB group. Blood and urine samples were collected at baseline and at 1, 2, 4, 5, 6 and 8 hr. Compared with the baseline, the IB group had a significantly increased urine output at 1 and 5 hr. The CRI group had a significantly increased urine output persisting for 4 hr compared with the baseline. Compared with the placebo group, 8-hr urine output and 8-hr sodium excretion were significantly increased in the IB and CRI groups; the values in the CRI group were significantly higher than those in the IB group. Eight-hour potassium excretion was significantly increased in the IB and CRI groups. The plasma aldosterone concentration was significantly elevated in the IB group at 8 hr. Duration of action may be a predominant cause of loop diuretic-related differences. Persistent diuresis may cause greater diuretic effects than transient diuresis, with less elevation of the plasma aldosterone concentration.KEY WORDS: canine, diuretic resistance, loop diuretics, plasma aldosterone concentrations.J. Vet. Med. Sci. 72(1): 13-18, 2010 Loop diuretics are recommended as a first-line therapy in the management of congestive heart failure (CHF) and are important in the symptomatic treatment [19]. They can be divided into short-acting ones, such as furosemide, and long-acting ones, such as azosemide and torasemide. Although furosemide is commonly used in clinical settings, its main complication is that patients with CHF develop resistance to loop diuretics due to a reduction in the glomerular filtration rate and an increase in sodium reabsorption at diuretic-insensitive sites in the nephron [6,10,11,28]. Additionally, furosemide activates the renin-angiotensinaldosterone (RAA) system and the sympathetic nervous system [14,16,32].In contrast to furosemide, previous studies have revealed that long-acting loop diuretics have clinical efficacy; they cause less activation of the RAA system, reduce diuretic resistance, improve ventricular fibrosis and decrease the mortality rate in both humans and animal models [7,17,23,37]. Furosemide treatment for 14 days leads to diuretic resistance in dogs, but this does not occur with torasemide [17]. In human clinical study, the myocardial collagen volume decreases with torasemide, but remains unchanged with furosemide [23]. Additionally, a recent study showed that torasemide is associated with lower mortality compared with furosemide in patients with CHF [7]. Similarly, our previous data suggested that azosemide causes mild and long...

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“…For this reason, the selective ARA eplerenone, which has a much lower affinity for the androgen receptor, has been developed. In humans, in terms of mineralocorticoid effects, 25 mg spironolactone is approximately equivalent to 50 mg eplerenone (Kalidindi et al, 2007) is a loop diuretic (Hori et al, 2007), registered in human medicine, which also appears to have a potassium sparing diuretic action, presumably through the antagonism of aldosterone. In the dog, however, although the diuretic actions of torasemide have been demonstrated (Uechi et al, 2003), the precise mode of its potassium sparing diuretic effect has not been clearly characterized in the published literature.…”

Section: Aldosterone Receptor Antagonistsmentioning

confidence: 99%

Aldosterone receptor antagonists - how cardiovascular actions may explain their beneficial effects in heart failure

Ovaert¹,

Elliott

Bernay³

et al. 2010

Journal of Veterinary Pharmacology and Therapeutics

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Ovaert, P., Elliott, J., Bernay, F., Guillot, E., Bardon, T. Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure. J. vet. Pharmacol. Therap.33, 109–117. Historically, aldosterone receptor antagonists (ARA) have been classified as ‘potassium sparing diuretics’. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end‐organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out‐with their diuretic effects.

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Effects of oral administration of furosemide and torsemide in healthy dogs

Abstract: In dogs, diuretic resistance developed after 14 days of furosemide, but not torsemide, administration; however, both loop diuretics were associated with increased BUN and plasma creatinine concentrations, compared with values before treatment.

Cited by 44 publications

References 31 publications

The Diuretic Torasemide Does Not Prevent Aldosterone-Mediated Mineralocorticoid Receptor Activation in Cardiomyocytes

The Diuretic Torasemide Does Not Prevent Aldosterone-Mediated Mineralocorticoid Receptor Activation in Cardiomyocytes

Differences in the Duration of Diuretic Effects and Impact on the Renin-Angiotensin-Aldosterone System of Furosemide in Healthy Dogs

Aldosterone receptor antagonists - how cardiovascular actions may explain their beneficial effects in heart failure

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