Calcium metabolism in uremic nephrocalcinosis: Preventive effect of verapamil

Goligorsky, Michael S.; Chaimovitz, Cidio; Rapoport, Jayson; Goldstein, Jed; Kol, R.

doi:10.1038/ki.1985.79

Cited by 58 publications

(16 citation statements)

References 17 publications

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“…The main site of its accumulation seems to be within the mitochondria (24). Recently it has been shown that verapamil, a potent calcium-channel blocker may prevent nephrocalcinosis (7). In our study we could not demonstrate any amelioration of gentamicin-induced nephrotoxicity by either kidney function indices or enzymatic-metabolic ones.…”

Section: Discussioncontrasting

confidence: 40%

“…Another aspect of calcium metabohsm Nephrotoxicity düe to aininoglycoside treatment is a in uraemia, namely nephrocalcinosis, was recently known clinical complication (1). Lietman et al (2) investigated by Goligorsky et al (7), who found that showed a fall in creatiiiine clearance in 15% of 214 verapamil prevents renal accumulation of calcium in patients treated with aminpglycosides. Factors that ufaemic rats.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Oral Calcium Load or Verapamil on Gentamicin-Induced Nephrotoxicity

Tamir

Israeli²,

Aladjem³

et al. 1989

Clinical Chemistry and Laboratory Medicine

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Summary: Several investigators haye reported recently that in rats, oral calcium load is associated with a marked ameliöration in gentamicin-induced renal failure. In contrast to these reports, using the same animal model, we could not observe calcium-induced moderation in gentamicin nephrotoxicity äs reflected by either urea or creatinine serum cöncentration or by various renal cortical intracellular enzymatic activities. Similarly, verapamil, a calcium channel blocker, had no effect on the degree of renal failure in these animals. We conclüde that maniptilätion of calcium diet may not be uniformly effective in reducing gentamicin nephrotoxicity. Additional nutritional factors may play a crucial role in achieving the ameliöration of this model of toxic nephropathy. Introduction...

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Section: Discussioncontrasting

confidence: 40%

Section: Introductionmentioning

confidence: 99%

The Effect of Oral Calcium Load or Verapamil on Gentamicin-Induced Nephrotoxicity

Tamir

Israeli²,

Aladjem³

et al. 1989

Clinical Chemistry and Laboratory Medicine

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“…Most prominent are the theories of hyperfiltration [23] and of mesangial overflow with macromolecules or toxic lipoproteins [29,30]. The present study does not allow us to draw any conclusions regarding other potentially harmful mechanisms such as simple hyperlipidaemia [27,31] or uraemic nephrocalcinosis [20]: plasma lipids at sacrifice showed unimportant differences between groups and overt nephrocalcinosis was not seen histologically.…”

Section: Discussioncontrasting

confidence: 39%

“…Protection against progressive chronic renal failure was thought to be due to a peculiar combination of unchanged glomerular capillary hypertension and increased proximal tubular pressure [19]. Histologically, this minute dose of verapamil had no effect on tubular morphology studied at 4 weeks [19] but appeared to prevent or delay uraemic nephrocalcinosis [20]. The two salient differences in experimental design, compared to the present study were the early start of verapamil treatment, which may have affected the period of remnant glomerular hypertrophy during the first 5 weeks after renal ablation, and more importantly the much smaller though parenterally applied dosage.…”

Section: Discussionmentioning

confidence: 99%

Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

Brunner

Bock

Hermle

et al. 1991

Nephrology Dialysis Transplantation

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Abstract. The effect of calcium channel blockers on the progression of renal failure is controversial. In contrast with earlier studies, we recently reported that moderately large doses of verapamil significantly accelerated chronic renal failure in the rat remnant kidney model [1]. Studies reporting beneficial effects of verapamil were characterised by a much lower dose of verapamil and by the start of treatment immediately after renal ablation, which potentially interfered with the initial phase of remnant kidney hypertrophy. We therefore studied the effects of a high, fully antihypertensive oral dose of verapamil (100-150 mg/kg/per day; group Vera high) and a low, haemodynamically almost ineffective dose (10-15 mg/kg per day; group Vera low), on the progression of chronic renal failure in female Wistar rats with 5/6 nephrectomy. The treatment was started no earlier than 5 weeks after renal ablation, and matched groups of 20 animals were followed for 16 weeks thereafter. High-dose verapamil reduced systolic blood pressure to median values of 130-140 mmHg throughout the experimental period, whereas blood pressure in Vera low animals remained elevated at median values of 165-172 mmHg similar to non-treated rats with 172-185 mmHg median systolic blood pressure.Despite control of hypertension, proteinuria increased more rapidly and to more elevated values in the Vera high animals (5.98 ± 0.91 mg/jumol creatinine before death/sacrifice) than in the Vera low and control groups (3.08 ± 0.91 and 3.60 ± 0.71 mg//imol creatinine, respectively, P < 0.05 vs Vera high), and signifiCorrespondence and offprint requests to: Professor F. P. Brunner, Kantonsspital Basel, 4031 Basel, Switzerland. cantly more animals died during the observation period in the Vera high compared to the control group (6 of 20 vs lof 20, P < 0.05). Kidney remnants were larger in the Vera high group, mainly due to tubulointerstitial changes with filling of dilated tubular lumina with proteinaceous casts. Mean glomerular diameter did not differ between groups, and the percentage of glomeruli with segmental or global glomerulosclerosis was not significantly increased in the Vera high group.It is concluded that chronic high-dose verapamil therapy in the 5/6 nephrectomy model, albeit effective in controlling hypertension, is deleterious to renal function when remnant hypertrophy has previously been allowed to occur. A low, haemodynamically barely effective, dose of verapamil fails to alter the course of renal failure in this setting.

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“…Indeed, the accumulation of mitochondrial Ca 2ϩ has been observed in the rat remnant kidney model (47), and it can be assumed that the accumulation of mitochondrial Ca 2ϩ contributes to the development of mitochondrial respiratory uncoupling, but the underlying mechanisms and their pathogenetic roles are still unclear and await further study.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Calcium Influx through L-Type Calcium Channels Attenuates Mitochondrial Injury and Apoptosis in Hypoxic Renal Tubular Cells

Tanaka

Nangaku

Miyata

et al. 2004

Journal of the American Society of Nephrology

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Abstract. In hypoxia, ATP depletion causes cellular Ca 2ϩ increase, mitochondrial injury, and apoptosis in renal tubular cells. However, the molecular basis of these observations is incompletely delineated. IRPTC, a rat renal proximal tubular cell line, was treated with antimycin A, and disturbances in cytoplasmic calcium ([Ca 2ϩ ]c) and mitochondrial calcium ion concentration ([Ca 2ϩ ]m), dissipation of mitochondrial membrane potential (⌬⌿ m ), cytochrome c release, and resultant apoptosis were examined. accumulation, mitochondrial permeability transition, cytochrome c release, caspase-9 activation, and resultant apoptosis (15.8 Ϯ 0.8% versus 8.9 Ϯ 0.7%; P Ͻ 0.01). Similar effects of azelnidipine were substantiated in an in vivo ischemia/reperfusion injury model. There were fewer terminal-deoxynucleotidyl transferase mediated dUTP nick-end labeling-positive cells in the azelnidipine-treated group (0.322 Ϯ 0.038/tubule) as compared with the vehicle-treated group (0.450 Ϯ 0.041; P Ͻ 0.05), although the antiapoptotic effect was smaller in vivo than in vitro, partly as a result of distinct levels of Bax expression. It is proposed that voltage-dependent Ca 2ϩ channels are involved in cellular and mitochondrial accumulation of Ca 2ϩ subsequent to ATP depletion and play an important role in regulating mitochondrial permeability transition, cytochrome c release, caspase activation, and apoptosis.Hypoxia is a complex stress marked by interrelated cellular changes such as ATP depletion, generation of reactive oxygen species (ROS), and elevation of intracellular Ca 2ϩ . In ischemia-reperfusion (I/R) injury, an initial decrease in cellular ATP causes an increase in extracellular potassium and intracellular sodium (1). The resultant depolarization of plasma membranes leads to Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels. A steep rise in intracellular Ca 2ϩ ([Ca 2ϩ ]c) is buffered to some degree by mitochondrial Ca 2ϩ uptake. However, once a continuous increase in [Ca 2ϩ ]c exceeds the buffering capacity, these organelles become dysfunctional via opening of a nonspecific pore in the mitochondrial membrane, the permeability transition (PT) pore. Mitochondrial Ca 2ϩ overload seems to be a consequence of the rise in the cytosolic Ca 2ϩ concentration promoted by Ca 2ϩ entry through plasma membrane receptor-operated and voltage-dependent Ca 2ϩ channels. The mitochondrial dysfunction contributes to apoptotic cell death, and increasing evidence suggests the relative importance of apoptotic cell death in the pathogenesis of ischemic acute renal failure (2-4). However, the molecular mechanism by which this occurs has remained elusive. It has been shown that agents that suppress calcium influx or buffer [Ca 2ϩ ]c can prevent apoptosis in several conditions (5-10), making this possibility an attractive explanation for the observations of apoptotic cell death in I/R injury.The mitochondrial PT is a crucial checkpoint in determining cell fate. The PT pore is putatively composed of the adenine nucleotide translocator...

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Calcium metabolism in uremic nephrocalcinosis: Preventive effect of verapamil

Cited by 58 publications

References 17 publications

The Effect of Oral Calcium Load or Verapamil on Gentamicin-Induced Nephrotoxicity

The Effect of Oral Calcium Load or Verapamil on Gentamicin-Induced Nephrotoxicity

Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

Blockade of Calcium Influx through L-Type Calcium Channels Attenuates Mitochondrial Injury and Apoptosis in Hypoxic Renal Tubular Cells

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