The influence of enalapril or spironolactone on experimental cyclosporin nephrotoxicity

McAuley, F. T.; Whiting, P. H.; Thomson, Angus W.; Simpson, John G.

doi:10.1016/0006-2952(87)90721-0

Cited by 28 publications

(15 citation statements)

References 16 publications

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“…A significant inhibition ofbody weight gain was observed in association with the rise in blood pressure. The decreased body weight gain is a previously recognized side effect of CysA administration in humans and animals (25,26), and could be accounted for by a reduction in food intake (not measured in this study) or by a catabolic effect of the drug as suggested by the elevation of plasma urea in CysA animals. Global reduction in food intake is unlikely to play a role in the pathogenesis ofCysA-induced hypertension, since chronic underfeeding has been reported to decrease blood pressure (27) is a possibility that the drug impairs the intestinal absorption of a specific nutrient critical to the control of systemic blood pressure, such as magnesium or calcium, thereby increasing blood pressure.…”

Section: Discussionmentioning

confidence: 77%

Vascular mechanisms of cyclosporin-induced hypertension in the rat.

Roullet¹,

Xue²,

McCarron³

et al. 1994

J. Clin. Invest.

101

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Numerous studies have explored the pathogenesis of cyclosporin A (CysA)-induced hypertension; however, none has assessed the impact of CysA treatment on resistance arteries in the setting of elevated blood pressure. Therefore, we studied the chronic effect of CysA on rat mesenteric artery resistance vessels (ex vivo). CysA (25 mg/kg per d for 7 d), but not vehicle, significantly raised systolic blood pressure (13.4±2.2 mmHg, P < 0.003, n = 9 per group). The resistance vessels from CysA-treated rats showed a small but significant decrease in norepinephrine sensitivity (P < 0.03) and a pronounced decrease in endothelium-dependent and -independent relaxation (P < 0.001) compared to controls. Endothelin-1 sensitivity tended to be diminished (P = 0.07). The direct (in vitro) effect of CysA was subsequently evaluated in resistance vessels from nontreated animals (n = 8) and exposed to CysA (2 ,ug/ml) for 24 h. As observed in vivo, CysA significantly decreased endothelium-dependent and -independent relaxations (P < 0.05) and attenuated norepinephrine sensitivity (P = 0.06). Methylene blue, a nitric oxide quencher, significantly inhibited the acetylcholine-induced relaxation in control, but not in CysA vessels, suggesting a selective action of CysA on the nitric oxide pathway. We conclude that CysA-induced hypertension is the consequence of a primary effect on resistance vessel relaxation, not increased vasoconstriction, as previously suggested. (J. Clin.

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Section: Discussionmentioning

confidence: 77%

Vascular mechanisms of cyclosporin-induced hypertension in the rat.

Roullet¹,

Xue²,

McCarron³

et al. 1994

J. Clin. Invest.

101

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“…Quantitative morphological analysis of renal tissue revealed a preventive effect of EPL on the progressive development of fibrosis and tubular loss relevant for the clinical setting [4-6,8]. In short-term studies, renal function, as measured by GFR, was reduced in CsA-treated animals when compared to controls, but partially preserved in animals in which the CsA treatment was combined with MR-receptor inhibitors [3-8]. The present study indicates that the protection of GFR by EPL is maintained during long-term treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Many treatment options have been examined with the purpose of countering these adverse effects, but until recently there have been no single pharmacological approach to prevent the gradual decline in renal function and the progressive renal fibrosis occurring during CsA treatment. There is solid evidence to indicate that aldosterone aggravates the CsA-induced nephrotoxicity [3-8] and consequently, that mineralocorticoid receptor (MR) blockade might have a preventive effect. In short-term animal studies (up to 21 days) the MR-antagonist spironolactone slowed the progression of renal dysfunction and reduced the morphological changes seen after CsA treatment in rats [3-7].…”

Section: Introductionmentioning

confidence: 99%

“…There is solid evidence to indicate that aldosterone aggravates the CsA-induced nephrotoxicity [3-8] and consequently, that mineralocorticoid receptor (MR) blockade might have a preventive effect. In short-term animal studies (up to 21 days) the MR-antagonist spironolactone slowed the progression of renal dysfunction and reduced the morphological changes seen after CsA treatment in rats [3-7]. The more selective MR antagonist eplerenone (EPL) antagonized the deterioration of renal function and blood pressure (BP) increase occurring in the early stage (21 days of treatment) of CsA-treated rats [8].…”

Section: Introductionmentioning

confidence: 99%

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The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

et al. 2013

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BackgroundChronic cyclosporine-(CsA)-mediated loss of kidney function is a major clinical problem in organ transplantation. We hypothesized that the mineralocorticoid receptor antagonist eplerenone (EPL) prevents chronic CsA-induced renal interstitial volume increase, tubule loss, and functional impairment in a rat model.MethodsSprague–Dawley rats received CsA alone (15 mg/kg/d p.o.), CsA and EPL (approximately 100 mg/kg/day p.o.) or vehicle (control) for 12 weeks. At 11 weeks, chronic indwelling arterial and venous catheters were implanted for continuous measurements of arterial blood pressure (BP) and GFR (inulin clearance) in conscious, freely moving animals. Plasma was sampled for analysis and kidney tissue was fixed for quantitative stereological analyses.ResultsCompared to controls, CsA-treatment reduced relative tubular volume (0.73±0.03 vs. 0.85±0.01, p<0.05) and increased relative interstitial volume (0.080±0.004 vs. 0.045±0.003, p<0.05); EPL attenuated these changes (0.82±0.02, p<0.05, and 0.060±0.006, p<0.05, respectively). CsA-treated rats had more sclerotic glomeruli and a higher degree of vascular depositions in arterioles; both were significantly reduced in CsA+EPL-treated animals. CsA increased BP and reduced body weight gain and GFR. In CsA+EPL rats, weight gain, GFR and BP at rest (daytime) were normalized; however, BP during activity (night) remained elevated. Plasma sodium and potassium concentrations, kidney-to-body weight ratios and CsA whole blood concentration were similar in CsA and CsA+EPL rats.ConclusionsIt is concluded that in the chronic cyclosporine rat nephropathy model, EPL reduces renal tissue injury, hypofiltration, hypertension, and growth impairment. MR antagonists should be tested for their renoprotective potential in patients treated with calcineurin inhibitors.

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“…One group received vehicle for 18 days and then vehicle plus spironolactone at 20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by gastric gavage for another 18 days (Sp) and the other group was treated with CsA for 18 days followed by CsA plus spironolactone for another 18 days (CsAϩSp). The dose of spironolactone has been proved to be enough to blockade MR in the rat (5,12,25,49).…”

Section: Methodsmentioning

confidence: 99%

Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity

Pérez‐Rojas¹,

Blanco²,

Cruz³

et al. 2007

American Journal of Physiology-Renal Physiology

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Recent studies from our laboratory have shown that the mineralocorticoid receptor (MR) blockade with spironolactone (Sp) prevented renal dysfunction and reduced renal injury in both acute and chronic cyclosporine (CsA) nephrotoxicity. This study was designed to evaluate whether Sp administration reduces functional and structural renal damage associated in the setting of preexisting chronic CsA nephrotoxicity. Twenty eight male Wistar rats were fed a low-sodium diet. Fourteen received vehicle (V) and the others were treated with CsA (15 mg/kg sc). After 18 days one half of each group received Sp (20 mg/kg po) for the subsequent 18 days. Creatinine clearance, arteriolopathy, tubulointerstitial fibrosis, arteriolar thickening, glomerular diameter, apoptosis index and TGF-beta, procaspase-3, and kidney injury molecule 1 (Kim-1) mRNA levels as well as Kim-1 shedding in urine were evaluated. Sp reduced the progression of renal dysfunction and tubulointerstitial fibrosis in preexisting chronic CsA nephrotoxicity. There was a significant reduction of arteriolar thickening in the CsA+Sp group that was associated with greater glomerular diameter and reduction of apoptosis index. These renoprotective effects were associated with reduction of TGF-beta, procaspase-3, and Kim-1 mRNA levels as well as Kim-1 shedding into the urine. In conclusion, MR blockade with Sp prevented the progression of renal injury in preexisting chronic CsA nephropathy. These results suggest that Sp may reduce CsA-induced established nephrotoxicity in patients.

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The influence of enalapril or spironolactone on experimental cyclosporin nephrotoxicity

Cited by 28 publications

References 16 publications

Vascular mechanisms of cyclosporin-induced hypertension in the rat.

Vascular mechanisms of cyclosporin-induced hypertension in the rat.

The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity

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