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Influence of muzolimine, a new diuretic, on experimental gentamicin nephrotoxicity
H Toutain1, B Olier, J P Fillastre
1INSERM-Unité 295, U.E.R. Médecine de Rouen, Université de Rouen, France.
Abstract:
The administration of diuretic drugs increases the nephrotoxicity of aminoglycosides. Muzolimine is a new diuretic which acts on the ascending limb of the loop of Henle and on the distal tubule. It differs from frusemide in its strong lipid binding and in its action at the antiluminal cellular pole. We attempted to determine whether muzolimine increases the nephrotoxicity of gentamicin. Four groups of Wistar rats were studied: one control group, one group treated with muzolimine (15 mg/kg), one group treated with gentamicin (20 mg/kg), and one group treated with gentamicin and muzolimine. Muzolimine induced a moderate but significant decrease in creatinine clearance, increased urinary excretion of n-acetyl-beta-D-glucosaminidase, and a slight decrease in lysosomal latency. The action of muzolimine did not reduce enzyme activities of the renal cortex (AAP, NAG, sphingomyelinase). Gentamicin induced functional renal modifications known to characterise nephrotoxicity of aminoglycosides. The association of muzolimine and gentamicin did not provoke a greater decrease of creatinine clearance or a greater decrease in enzyme activities of the renal cortex. In conclusion, muzolimine does not seem to potentiate the nephrotoxic action of gentamicin. However, we note that the association of muzolimine and gentamicin provoked a greater decrease in mitochondrial oxygen consumption than that provoked by gentamicin alone. It also induced more marked reduction of the activity of renal sphingomyelinase. This point is important when it is considered that the appearance of myelin bodies in the renal cortex is secondary to the decrease of this enzyme.
Insights
Muzolimine, a new diuretic, did not worsen gentamicin-induced kidney damage in rats. However, the combination reduced mitochondrial oxygen consumption and renal sphingomyelinase activity.
Area of Science:
- Pharmacology
- Nephrology
- Toxicology
Background:
- Diuretic drugs can increase the nephrotoxicity of aminoglycosides.
- Muzolimine is a novel diuretic acting on the loop of Henle and distal tubule, with distinct properties from frusemide.
- Aminoglycosides, like gentamicin, are known to cause nephrotoxicity.
Purpose of the Study:
- To investigate whether the diuretic muzolimine potentiates the nephrotoxic effects of gentamicin.
- To evaluate the impact of muzolimine and gentamicin co-administration on renal function and enzyme activity in rats.
Main Methods:
- Four groups of Wistar rats were used: control, muzolimine alone, gentamicin alone, and combined muzolimine and gentamicin.
- Renal function was assessed by measuring creatinine clearance.
- Urinary and renal cortical enzyme activities (n-acetyl-beta-D-glucosaminidase, AAP, NAG, sphingomyelinase) and mitochondrial oxygen consumption were analyzed.
Main Results:
- Muzolimine alone caused a moderate decrease in creatinine clearance and increased urinary n-acetyl-beta-D-glucosaminidase excretion.
- Gentamicin induced characteristic functional renal modifications indicative of nephrotoxicity.
- Combined muzolimine and gentamicin did not result in a greater decrease in creatinine clearance or renal cortical enzyme activities compared to gentamicin alone.
Conclusions:
- Muzolimine does not appear to potentiate the nephrotoxic action of gentamicin.
- The combination of muzolimine and gentamicin led to a more significant reduction in mitochondrial oxygen consumption and renal sphingomyelinase activity than gentamicin alone.
- The observed decrease in renal sphingomyelinase activity may be linked to the formation of myelin bodies in the renal cortex.