1994
DOI: 10.2131/jts.19.4_219
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Tacrolimus (Fk506)-induced nephrotoxicity in spontaneous hypertensive rats.

Abstract: To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the… Show more

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Cited by 31 publications
(23 citation statements)
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“…In another in vivo-model, acute bolus Nielsen et al could demonstrate a predominantly preglomerular effect of tacrolimus with a marked reduction of inulinclearance as marker for GFR after a four-week administration in rats [16]. Experiments in spontaneous hypertensive rats have pointed out associated increases of plasma renin activity and urinary thromboxane excretion and decreased prostacyclin-metabolite-excretion together with a decrease in creatinine-clearance after CNI-administration [14]. Involvement of serotoninergic pathways has been suspected as one mediator of vasoconstriction and diminished renal blood flow [15].…”
Section: Introductionmentioning
confidence: 96%
“…In another in vivo-model, acute bolus Nielsen et al could demonstrate a predominantly preglomerular effect of tacrolimus with a marked reduction of inulinclearance as marker for GFR after a four-week administration in rats [16]. Experiments in spontaneous hypertensive rats have pointed out associated increases of plasma renin activity and urinary thromboxane excretion and decreased prostacyclin-metabolite-excretion together with a decrease in creatinine-clearance after CNI-administration [14]. Involvement of serotoninergic pathways has been suspected as one mediator of vasoconstriction and diminished renal blood flow [15].…”
Section: Introductionmentioning
confidence: 96%
“…15 These results suggest that the mechanism of kidney dysfunction is mainly vascular, although a toxic effect on the epithelial cells cannot be ruled out. 17 A direct effect of arteriolar vasoconstriction has been demonstrated, 17 which involves a reduction in PGI2 synthesis and an increase in endothelin production. 18,19 Tacrolimus has been shown to perturb the homeostasis of intracellular calcium in smooth muscle via the drug-calcineurin complex, encouraging arteriolar constriction; in fact, the administration of calcium antagonists (diltiazem and verapamil) may in reduce the vasoconstrictive effects and the degree of functional disturbance in animal models.…”
Section: Discussionmentioning
confidence: 99%
“…18,19 Tacrolimus has been shown to perturb the homeostasis of intracellular calcium in smooth muscle via the drug-calcineurin complex, encouraging arteriolar constriction; in fact, the administration of calcium antagonists (diltiazem and verapamil) may in reduce the vasoconstrictive effects and the degree of functional disturbance in animal models. [13][14][15][16][17][18][19][20][21] The loss of adrenergic balance due to a direct action of calcineurin on alpha receptors and the appearance of hypertrophy of the juxtaglomerular apparatus and other mechanisms that may produce a loss of renal vascular regulation causes by this drug. [13][14][15][16][17][18][19][20][21][22] The range of morphologic lesions is varied depending largely on the exposure time; vacuolization of the arterial tunica media (arteriolopathy), isometric vacuolization of the proximal tubule and hypertrophy of the juxtaglomerular apparatus are early lesions, whereas hypertrophy of the intima, mucoid deposits, glomerular hyalinosis and tubular atrophy with radial fibrosis have a later onset.…”
Section: Discussionmentioning
confidence: 99%
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