Modulation of gentamicin nephrotoxicity by chronic inhibition of angiotensin-I-converting enzyme in rat

Abstract

Perindopril, a new specific and potent inhibitor of angiotensin-I-converting enzyme, was used to evaluate the possible participation of inhibition of the renin-angiotensin system in the development of aminoglycoside-induced renal failure. Kidney function, morphology and biochemistry were evaluated at regular intervals throughout the study. Perindopril was given orally to rats at a daily dose of 2 mg/kg for 15 days prior to and during 15-day gentamicin treatment given intraperitoneally at a daily dose of 50 mg/kg. Perindopril treatment alone induced no modification in renal function or structure. Gentamicin treatment alone induced typical renal lesions which were scored as moderate and a slight but significant decrease in ACE blood levels. Concurrent treatment with perindopril and gentamicin induced a greater drop in ACE blood levels than after the administration of perindopril alone and produced more marked renal impairment than after the administration of gentamicin alone. These observations suggest that the integrity of the renin-angiotensin system may play an important role in limiting kidney injury during aminoglycoside-induced nephrotoxicity.

Gentamicin Reduces Serum ACE Activity in Patients with Normal Kidney Function

“…One reason for these contradictory reports is the limited sensitivity of the most commonly used indicator of aminoglycoside nephrotoxicity, that is, the increase in serum creatinine. Extensive alteration of proximal tubular cells can be observed long before this parameter is modified [10].…”

“…In rats toxic levels of gentamicin reduce serum ACE activity slightly [10]. In rat acute renal failure caused by mercuric chloride, potassium dichromate, and uranyl nitrate increased serum ACE activity significantly [16][17][18].…”

“…In patients with acute renal failure (ARF), serum ACE levels have been noted to be low during the acute phase of illness [9], and to return to normal levels with recovery. In rats, administration of intra peritoneal gentamicin 50 mg/kg/ day causes a slight but significant reduction in serum ACE activity [10].…”

The Nephrotoxicity of Concurrent Use of Enalapril and Gentamicin in Rats

“…Improvement in the functional deteriorations and renal damage induced by GM was observed after the administration of captopril that leads to suppression of progression of GM nephrotoxicity; this amelioration was related to the captopril potentiality to augmented bradykinin deliberation that leads to "vasodilator" which motivates prostaglandin production, ensuring an enlargement of the intrarenal blood vessels, and leading to an amelioration in the glomerular hemodynamic and preservation of the kidney from nephrotoxicity [15,31]. On the other hand, other studies have shown that ACEI increase GM nephrotoxicity, the concurrent treatment with perindopril and GM-induced a greater renal impairment than after the administration of GM alone [32], captopril has been found to increase GM nephrotoxicity and progressively decreased the creatinine clearance in rats [33], captopril also aggravated the detrimental consequence of GM on the renal function in rats depleted of potassium [13]. Captopril was also accompanied by a reduction of creatinine clearance and a decrease in excretion of cyclic GMP in hypertensive rats [34].…”